Spiro-tricyclicaromatic succinimide derivatives as inhibitors of aldose reductase

ABSTRACT

Disclosed are substituted or unsubstituted planar tricyclic fluorene or nuclear analogs thereof, spiro-coupled to a five-membered ring containing a secondary amide, and the pharmaceutically acceptable salts thereof. These compounds are useful, inter alia in the treatment of diabetes. Also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when indicated for, inter alia, long term, prophylactic treatment of the diabetes syndrome. A particularly preferred class of compounds comprise difluoro-dialkoxy substituted spiro-(9H-fluorene-9,4&#39;-imidazolidine)-2&#39;,5-diones.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 402,035 filed Sep. 5, 1989,now U.S. Pat. No. 5,070,100, which is a continuation-in-part of Ser. No.07/094,636, filed Sep. 9, 1987, which is a continuation-in-part of Ser.No. 07/005,859, filed Jan. 21, 1987, now U.S. Pat. No. 4,864,028, issuedSep. 5, 1989 (now abandoned), which is a continuation of Ser. No.06/766,569, filed Aug. 14, 1985 (now abandoned), which is a continuationof Ser. No. 06/532,168, filed Sep. 14, 1983, now U.S. Pat. No.4,537,892.

FIELD OF THE INVENTION

This invention relates to novel spiro-tricyclicaromatic succinimidederivatives and related spiro-heterocyclic analogs such asspiro-tricyclicaromatic-thiazolidine-dione, -imidazolidinedione, and-oxazolidine-dione derivatives. More particularly, the invention relatesto spiro-tricyclicaromatic succinimide derivatives and relatedspiro-heterocyclic analogs which are useful to prevent diabeticcataract, nerve tissue damage, and certain vascular changes.

BACKGROUND ART

As disclosed in U.S. Pat. No. 3,821,383, aldose reductase inhibitorssuch as 1,3-dioxo-1H-benz [d,e]-isoquinoline-2-(3H)-acetic acid, and itsderivatives, are useful as inhibitors of aldose reductase andalleviators of diabetes mellitus complications.Spiro-[chroman-4,4'-imidazolidine]-2',5'-dione andspiro-[imidazolidine-4,4'-thiochroman]-2,5-dione and their derivatives,disclosed in U.S. Pat. No. 4,130,714 and U.S. Pat. No. 4,209,630, arealso indicated as being useful in this regard. Certainspiro-polycyclicimidazolidinedione derivatives from U.S. Pat. No.4,181,728 have been demonstrated to have inhibitory activity againstaldose reductase and polyol accumulation. U.S. Pat. No. 4,117,230describes a series of spiro-hydantoin compounds which include the6-fluoro and 6,8-dichloro derivatives of spiro-chromanimidazolidmediones. Spiro-fluorenhydantoin and its derivatives aredisclosed in my prior U.S. Pat. Nos. 4,438,272 and 4,436,745, as beingpotent human and rat aldose reductase inhibitors which prevent polyolaccumulation in lenticular and nervous tissues of diabetic andgalactosemic rats and prevent cataract and nerve dysfunction in diabeticrats. Pan et al, J. Med. Chem. 7, 31-38 (1964), describeshalogenofluorenes as potential antitumor agents, and Pan et al, J. Med.Chem. 10, 957-959 (1967), describes spiro[fluoren-9,4'-imidazolidine]-2',5'-diones as potential antitumor agents.

SUMMARY OF THE INVENTION

It is one object of the invention to provide a novel series ofspiro-tricyclicaromatic succinimide derivatives and relatedspiro-heterocyclic analogs, and methods for their preparation, whichcompounds are useful as inhibitors of aldose reductase and alleviatorsof diabetes mellitus complications.

A still further object of the invention is to provide pharmaceuticalcompositions and methods for inhibiting aldoreductase and the treatmentof diabetes mellitus wherein the active ingredient comprises aspiro-tricyclicaromatic succinimide derivative or spiro-heterocyclicanalog.

Other objects and advantages of the present invention will becomeapparent as the description thereof proceeds.

In satisfaction of the foregoing objects of the invention, there isprovided by the broadcast embodiment of the invention, substituted orunsubstituted planar tricyclic fluorene or nuclear analogs thereof,spiro-coupled to a five-membered ring containing a secondary amide, andthe pharmaceutically acceptable salts thereof.

In further satisfaction of the foregoing objects and advantages, thereare provided by the present invention spiro-tricyclic-aromatic imides ofthe formula: ##STR1## and the pharmaceutically acceptable metal saltsand in cases, where the basic aromatic nitrogens are in the A, and/or Bring, the pharmaceutically acceptable organic and inorganic saltsthereof, wherein A and B are aromatic or heterocyclic rings connectedthrough two adjacent positions to a central five-membered ring, the Aand B rings being selected from the group consisting of those of theformula: ##STR2## and wherein U is selected from the group consisting ofO, S, N-R¹ ;

X is selected from the group consisting of H, F, lower alkyl sulfide(e.g., --S--CH₃), lower alkylsulfinyl (e.g., --S(O)CH₃);

Y is selected from the group consisting of H, --OH, and ##STR3## F, Cl,lower alkyl, lower alkoxy, lower alkylsulfide (e.g., --S--CH₃), loweralkylsulfinyl (e.g., --S(O)--CH₃), lower alkylsulfonyl (e.g., --SO₂CH₃), --CF₃, --S--CF₃, --SO₂ CF₃, CO--N(R¹)--R², lower alkyl alcohol(e.g., --CH₂ --OH), lower alkyl ether (e.g., --CH₂ OCH₃), nitro, loweralkyl sulfide lower alkyl (e.g., --CH₂ S--CH₃), lower alkylamine (e.g.,--CH₂ NH₂), lower alkyl esters (e.g., --CH₂ --O--COCH₃), carboxylicacids and lower alkyl esters (e.g., --COOR³), lower alkyl carboxylicacids and esters (e.g., --CH(CH₃)--COOR¹), lower cycloalkyl (e.g.,cyclopropyl); provided that when both of Rings A and B are phenyl, andone of X or Y is H or F, the other of X or Y must be other than H or F;

R¹ and R² are selected from the group consisting of H and lower alkyl(preferably methyl or ethyl);

R³ is lower alkyl (preferably methyl or ethyl);

Z is selected from the group consisting of H, lower alkyl (preferablymethyl), and halogen (fluoro, chloro, bromo, iodo); and

t is selected from the group consisting of NH, O, S, and CHR¹. Loweralkyl is defined as containing six or less carbon atoms.

Also provided are methods for preparation of the above describedcompounds, pharmaceutical compositions containing these compounds as theactive ingredient, and methods for treatment of diabetic cataract, nervetissue damage, and certain vascular changes utilizing the abovedescribed compounds as the active ingredient.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is concerned with novel spiro-tricyclicaromaticsuccinimide derivatives and related spiro-heterocyclic analogs such asspiro-tricyclicaromatic-thiazolidinedione, -imidazolidinedione, and-oxazolidinedione derivatives. The invention is also concerned withmethods for preparation of these compounds, and methods for treatment ofdiabetic cataract, nerve tissue damage, and certain vascular changesusing pharmaceutical compositions containing the compounds of thepresent invention as the active ingredient.

The compounds of the present invention are inhibitors of the enzymealdose reductase and, while applicant is not bound by any theory, thepharmaceutical utility of the compounds of the present invention appearsto correlate with their observed aldoreductase inhibitory property. Theinhibition of the enzyme aldose reductase and related reductases resultsin the inhibition of abnormal polyol accumulation at the expense ofNADPH in those tissues containing aldose reductase and/or relatedaldehyde reductases. The inhibition of the formation of a polyol, suchas sorbitol or galactitol, arising from the reduction of an aldose, suchas glucose or galactose respectively, is believes beneficial to delaythe progression of certain complications arising from hyperglycemia orhypergalactocemia. Hyperglycemia is associated with the complications ofneuropathy, retinopathy, cataract, glaucoma, and impaired wound healingin diabetes mellitus patients.

According to U.S. Pat. No. 3,821,383, aldose reductase inhibitors suchas 1,3-dioxo-1H-benz [d,e]-isoquinoline-2-(3H)-acetic and itsderivatives are useful as inhibitors of aldose reductase and alleviatorsof diabetes mellitus complications.Spiro-[chroman-4,4'-imidazolidine]-2',5'-dione andspiro-[imidazolidine-4,4'-thichroman]-2,5-dione and their derivativesfrom U.S. Pat. No. 4,130,714 and U.S. Pat. No. 4,209,630 have alsoproven useful in this regard. Certain spiro-polycyclicmidazolidinedionederivatives from U.S. Pat. No. 4,181,728 have been demonstrated to haveinhibitory activity against aldose reductase and polyol accumulation.Spiro-fluorenhydantoin and its derivatives, according to theabove-mentioned U.S. Pat. Nos. 4,438,272 and 4,436,745, are potent humanand rat aldose reductase inhibitors which prevent polyol accumulation inlenticular and nervous tissues of diabetic and galactosemic rats andprevent cataract and nerve dysfunction in diabetic rats. Such compoundsinhibit the reduction of aldoses such as glucose and galactose tosorbitol and galactitol, thus preventing the harmful accumulation ofpolyols in certain nervous, ocular, and vascular tissues. Effectivealdose reductase inhibitor chemotherapy prevents, improves, or delaysthe onset, duration or expression of certain sequelae of diabetesmellitus which include ocular sequelae (e.g., cataract and retinopathy),kidney damage (nephropathy), neurological dysfunction (e.g., peripheralsensory neuropathy), vascular disease (e.g., diabetic micro- andmacro-vasculopathies), impaired wound healing (e.g., impaired cornealreepithelialization) and heart disease. The discussion of the aldosereductase utility as described in U.S. Pat. No. 4,209,630 is herebyincorporated herein by reference.

As a result, the compounds of the present invention are of significantvalue as aldose reductase inhibitors, since it is already known in theart that aldose reductase inhibitors prevent diabetic cataract, nervetissue damage, and certain vascular changes.

In accordance with the present invention, it has been surprisingly foundthat various spirocyclic imide containing derivatives of the tricyclefluorene and related heterocyclic analogs of fluorene and theirderivatives are extremely useful as inhibitors of aldose reductase,especially human aldose reductase.

The spiro-cyclic aromatic imides of the present invention may bedescribed by the following general formula: ##STR4## and thepharmaceutically acceptable metal salts and in cases, where basicaromatic nitrogens are in the A, and/or B rings, the pharmaceuticallyacceptable organic and inorganic acid salts thereof, wherein A and B arearomatic or heterocyclic rings connected through two adjacent positionsto a central cycloalkyl ring, the A and B rings being selected from thegroup consisting of those of the formula: ##STR5## and wherein U isselected from the group consisting of O, S, N--R¹ ;

X is selected from the group consisting of H, F, lower alkyl sulfide(e.g., --S--CH₃), lower alkylsulfinyl (e.g., --S(O)CH₃);

Y is selected from the group consisting of H, --OH, and ##STR6## F, Cl,lower alkyl, lower alkoxy, lower alkylsulfide (e.g., --S--CH₃), loweralkylsulfinyl (e.g., --S(O)--CH₃), lower alkylsulfonyl (e.g., --SO₂CH₃), --CF₃, --S--CF₃, --SO₂ CF₃, CO--N(R¹)--R², lower alkyl alcohol(e.g., --CH₂ --OH), lower alkyl ether (e.g., --CH₂ OCH₃), nitro, lowerakyl sulfide lower alkyl (e.g., --CH₂ S--CH₃), lower alkylamine (e.g.,--CH₂ NH₂), lower alkyl esters (e.g., --CH₂ --O--COCH₃), carboxylicacids and lower alkyl esters (e.g., --COOR³), lower alkyl carboxylicacids and esters (e.g., --CH(CH₃)--COOR¹), lower cycloalkyl (e.g.,cyclopropyl); provided that when both of Rings A and B are phenyl, andone of X or Y is H or F, the other of X or Y must be other than H or F;

R¹ and R² are selected from the group consisting of H and lower alkyl(preferably methyl or ethyl);

R³ is lower alkyl (preferably methyl or ethyl);

Z is selected from the group consisting of H, lower alkyl (preferablymethyl), and halogen (fluoro, chloro, bromo, iodo); and

t is selected from the group consisting of NH, O, S, and CHR¹.

In a more preferred embodiment, the spiro-cyclic aromatic imides of thepresent invention are of the following general formula: ##STR7## whereinA, B, U, X, Y, R¹, R², R³, Z, and t are as described above. In morepreferred embodiments, the cycloalkyl groups have 4 to 7 carbon atomsand lower alkyl groups have 1 to 6 carbon atoms. In an especiallypreferred embodiment, Ring A is selected from the foregoing group andRing B is selected from the group consisting of the following: ##STR8##where X, U, and Z are described above. In the compounds of Formulae Iand I-A, Rings A and B are attached to the central five-membered ring atpositions 1,2 and 3,4.

The compounds of the present invention have important geometric andchemical similarities. These similarities include a planar, rigidtricyclic fluorene or fluorene-like aromatic ring system spiro-coupledto a five-membered imide (or cyclic secondary amide) ring such assuccinimide, hydantoin, thiazolidinedione or oxazolidinedione. Thesespirocyclic derivatives of the various tricycles each contain apolarizable and hydrogen-bondable secondary amide, also called imide,radical (--CO--NH--CO--).

In those instances where, according to general Formulae I and I-A, Adoes not equal B, the spiro carbon is chiral. Activity of any suchracemic mixture may be attributable to only one isomer. Resolution, ordirect synthesis, of the enantiomers, as is known in the art, isrecognized as a method to isolate or prepare the active or the moreactive enantiomer. It is also recognized that certain patterns ofsubstitution on A and/or B according to Formulae I and I-A may createasymmetry, and the resulting diastereomeric mixtures may be separated bychromatography or solvent recrystallizations, as is known and practicedin the art. For example, if A has a methylsulfoxyl substituent and A isdifferent from B, then there are at least two chiral centers: the spirocarbon and the sulfoxide sulfur. Physical separation of thisdiastereomeric mixture by chromatography or other methods practiced inthe art will yield two racemic mixtures, each containing a pair ofenantiomers. Stereospecific oxidation of a methylsulfido on A to yield amethylsulfoxide (e.g., via sodium metaperiodate and albumin) when A isdifferent than B (according to Formula I) will yield a diastereomericmixture, which then can be separated by conventional physical methodsknown in the art, such as liquid chromatography or differential solventsolubility, to yield the purified diastereomers which are themselvespurified optical isomers. Reduction of the two optically activesulfoxide diastereomers will yield the optically active pair ofenantiomers or mirror image isomers.

Of special interest in this invention are typical and preferred specieof Formula I such as these racemic mixtures:spiro-(6-fluoro-4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione;spiro-(7-fluoro-9H-pyrrolo[1,2-a]indol-9,4'-imidazolidine)-2',4'-dione;spiro-(2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione;spiro-(6-fluoro-8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione;spiro-(2-fluoro-9H-fluoren-9,3'-succinimide);spiro(2-fluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione;spiro-(7-fluoro-9H-indeno[2,1c]pyridin-9,4'-imidazolidine)-2',5'-dione;spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione;spiro-(7-fluoro-5H-indeno[1,2-c]pyridin-5,4'-imidazolidine)-2',5'-dione;spiro-(7-fluoro-9H-indeno[2,1-b]pyridin-5,4'-imidazolidine)-2',5'-dione;spiro-(7-fluoro-5H-indeno[1,2-c]pyridin-5,5'-thiazolidine)-2',4'-dione;spiro-(7-fluoro-5H-indeno[1,2-b] pyridin-5,5'-thiazolidine)-2',4'-dione;spiro-(7-fluoro-9H-indeno[2,1-c]pyridin9,5'-thiazolidine)-2',4'-dione;spiro-(7-fluoro-9H-[2,1-b]pyridin-9,5'-thiazolidine)-2',4'-dione;spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,3'-succinimide;spiro-(7-chloro-5H-[1,2-b]pyridin-5,5'-thiazolidine)-2',4'-dione;spiro-(7-chloro-5H-[1,2-b]pyridin-5,5'-oxazolidine)-2',4'-dione;spiro-(6-fluoro-4H-indeno[1,2-b]thiophen-4,5'-thiazolidine)-2',4'-dione;spiro-(6-chloro8 H-indeno[2,1-b]thiophen-8,5'-thiazolidine)-2',4'-dione;spiro-(2-fluoro,7-methylthiol-9H-fluoren-9-,5'-thiazolidine)-2',4'-dione.

The compound of Formula I identified below by means of both linearnomenclature and structural formulas are also of special interest:

    __________________________________________________________________________    COM-                                                                          POUND                                                                              NAME                                                                     __________________________________________________________________________     1   2-METHYL-7-FLUOROSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,4'-IMIDAZOLI         DINE]-2',5'-DIONE                                                         2   2-METHYL-7-FLUOROSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,5'-OXAZOLIDI         NE]-2',4'-DIONE                                                           3   2,7-DIFLUORO-4-METHYLSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDINE]-2',5         '-DIONE (IC50 = 2.8 × 10.sup.-9  --M)*                              4   7,9-DIFLUORO-2-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,3'-PYRRO         LIDINE]-2,',5'-DIONE                                                      5   2,7-DIFLUORO-4-METHYLSPIRO[9 .sub.--H-FLUORENE-9,5'-THIAZOLIDINE]-2',         4'-DIONE                                                                  6   2,4,5,7-TETRAFLUOROSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDINE]-2',5'-         DIONE                                                                     7   2,4,5,7-TETRAFLUOROSPIRO[9 .sub.--H-FLUORENE-9,5'-THIAZOLIDINE]-2',4'         -DIONE (IC50 = 1.7 × 10.sup.-8  --M)*                               8   2,4,5,7-TETRAFLUOROSPIRO[9 .sub.--H-FLUORENE-9,5'-OXAZOLIDINE]-2',4'-         DIONE                                                                     9   2,4,5,7-TETRAFLUOROSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLIDINE]-2',5         '-DIONE (IC50 = 1.2 × 10.sup.-8  --M)*                             10   2,7-DIFLUORO-4-METHYLSPIRO[9 .sub.--H-FLUORENE-9,5'-OXAZOLIDINE]-2',4         '-DIONE                                                                  11   2,7-DIFLUORO-4-METHYLSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLIDINE]-2'         ,5' -DIONE (IC50 = 1.28 × 10.sup.-8  --M)*                         12   7,9-DIFLUOROSPIRO[5 .sub.--H-INDENTO[1,2-c]PYRIDIN-5,3'-PYRROLIDINE]-         2',5'-DIONE                                                              13   7,9-DIFLUOROSPIRO[5 .sub.--H-INDENO[1,2-c]PYRIDIN-5,4'-IMIDAZOLIDINE]         -2',5'-DIONE                                                             14   7,9-DIFLUOROSPIRO[5 .sub.--H-INDENO[1,2-c]PYRIDIN-5,5'-OXAZOLIDINE]-2         ',4'-DIONE                                                               15   2,7-DIFLUORO-4-METHOXYSPIRO]9 .sub.--H-FLUORENE-9,5'-OXAZOLIDINE]-2',         4'-DIONE                                                                 16   2,7-DIFLUORO-4-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLIDINE]-2         ',5'-DIONE (IC50 = 9.4 × 10.sup.-9  --M)*                          17   2,7-DIFLUORO-4-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDINE]-2',         5'-DIONE (IC50 = 4.8 × 10.sup.-9  --M)*                            18   2,7-DIFLUORO-4-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,5'-THIAZOLIDINE]-2'         ,4'-DIONE                                                                19   2,4,7-TRIFLUORO-5-METHYLSPIRO[9 .sub.--H-FLUORENE-9,5'-THIAZOLIDINE]-         2',4'-DIONE                                                              20   2,9-DIFLUORO-2-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,5'-OXAZO         LIDINE]-2',4'-DIONE                                                      21   7,9-DIFLUORO-2-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,3'-PYRRO         LIDINE]-2',5'-DIONE                                                      22   7,9-DIFLUORO-2-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,4'-IMIDA         ZOLIDINE]-2',5'-DIONE (IC50 =                                                 4.8 × 10.sup.-8   --M)*                                            23   2,4,7-TRIFLUORO-5-METHYLSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDINE]-2         ',5'-DIONE                                                               24   2,4,7-TRIFLUORO-5-METHYLSPIRO[9 .sub.--H-FLUORENE-9,5'-OXAZOLIDINE]-2         ',4'-DIONE                                                               25   2,4,7-TRIFLUORO-5-METHYLSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLIDINE]         -2',5'-DIONE                                                             26   2,4,7-TRIFLUORO-5-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,5'-THIAZOLIDINE]         -2',4'-DIONE                                                             27   2,4,7-TRIFLUORO-5-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDINE]-         2',5'-DIONE                                                              28   2,4,7-TRIFLUORO-5-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLIDINE         ]-2',5'-DIONE (IC50 = 1.13 × 10.sup.-5  --M)*                      29   2,4,7-TRIFLUORO-5-METHOXYSPIRO[9 .sub.--H-FLUORENE-9,5'-THIAZOLIDINE]         -2',4'-DIONE                                                             30   2,4,7-TRIFLUORO-5-METHYLTHIOSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDIN         E]-2',5'-DIONE                                                           31   2,4,7-TRIFLUORO-5-METHYLTHIOSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLID         INE]-2',5'-DIONE                                                         32   2,7-DIFLUORO-4-METHYLSULFINYLSPIRO[9 .sub.--H-FLUORENE-9,5'-OXAZOLIDI         NE]-2',4'-DIONE                                                          33   2,4,7-TRIFLUORO-5-METHYLTHIOSPIRO[9 .sub.--H-FLUORENE-9,5'-OXAZOLIDIN         E]-2',4'-DIONE                                                           34   2,7-DIFLUORO-4-METHYLTHIOSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLIDINE         ]-2',5'-DIONE (IC50 = 1.75 × 10.sup.-8  --M)*                      35   2,7-DIFLUORO-4-METHYLSULFINYLSPIRO[9 .sub.--H-FLUORENE-9,4'-IMIDAZOLI         DINE]-2',5'-DIONE                                                        36   2,7-DIFLUORO-4-METHYLTHIOSPIRO[9 .sub.--H-FLUORENE-9,5'-OXAZOLIDINE]          -2',4'-DIONE                                                             37   2,7-DIFLUORO-4-METHYLSULFINYLSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDI         NE]-2',5'-DIONE                                                          38   2,7-DIFLUORO-4-METHYLTHIOSPIRO[9 .sub.--H-FLUORENE-9,3'-PYRROLIDINE]-         2',5'-DIONE                                                              39   3,7-DIFLUORO-9-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,5'-THIAZ         OLIDINE]-2',4'-DIONE                                                     40   3,7-DIFLUORO-9-METHYLTHIOSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,5'-T         HIAZOLIDINE]-2',4'-DIONE                                                 41   3,7-DIFLUORO-9-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,3'-PYRRO         LIDINE]-2',5'-DIONE                                                      42   7-FLUORO-5-METHYLTHIOSPIRO[9 .sub.--H-PYRROLO[1,2-a]INDOL-9,4'-IMIDAZ         OLIDINE]-2',5'-DIONE                                                     43   3,7-DIFLUORO-9-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,4'-IMIDA         ZOLIDINE]-2',5'-DIONE (IC50 =                                                 1.61 × 10.sup.-8  .sub.--M)*                                       44   3,7-DIFLUORO-9-METHYLTHIOSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,3'-P         YRROLIDINE]-2',5'-DIONE                                                  45   3,7-DIFLUORO-9-METHYLSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,5'-OXAZO         LIDINE]-2',4'-DIONE                                                      46   3,7-DIFLUORO-9-METHYLTHIOSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,5'-O         XAZOLIDINE]-2',4'-DIONE                                                  47   3,7-DIFLUORO-9-METHYLTHIOSPIRO[5 .sub.--H-INDENO[1,2-b]PYRIDIN-5,4'-I         MIDAZOLIDINE]-2',5'-DIONE                                                48   5,7-DIFLUORO-2-METHYLTHIOSPIRO[9 .sub.--H-PYRROLO[1,2-a]INDOL-9,4'-IM         IDAZOLIDINE]-2',5'-DIONE                                                 49   5,7-DIFLUORO-3-METHYLSPIRO[9 .sub.--H-PYRROLO[1,2-a]INDOL-9,4'-IMIDAZ         OLIDINE]-2',5'-DIONE                                                     50   7-FLUORO-5-METHOXYSPIRO[9  .sub.--H-PYRROLO[1,2-a]INDOL-9,4'-IMIDAZOL         IDINE]-2',5'-DIONE                                                       51   5,7-DIFLUORO-2-METHYLSULFINYLSPIRO[9 .sub.--H-PYRROLO[1,2-a]INDOL-9,4         '-IMIDAZOLIDINE]-2',5'-DIONE                                             52   7-FLUORO-5-METHYLSPIRO[9 .sub.--H-PYRROLO[1,2-a]INDOL-9,4'-IMIDAZOLID         INE]-2',5'-DIONE                                                         __________________________________________________________________________    *IC50 values are based on inhibition of rat lens aldose reductase.             ##STR9##                                                                      ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                     ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                     ##STR20##                                                                     ##STR21##                                                                    Also of special interest in this invention are these achiral or               nonracemic compounds: spiro-( 2,7-difluoro-9H-fluoren-9,4'-imidazolidine)-    ',5'-dione; spiro-(2,7-difluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione;     spiro-(2,7-difluoro-9H-fluoren-9,3'-succinimide); spiro-(2,7-difluoro-9H-    fluoren-9,5'-oxazolidine)-2',4'-dione. All the aforementioned compounds       are highly potent as regards their aldose reductase inhibitory                activities. All of the aforementioned preferred compounds as in Formula I     may be formulated as the base salts thereof with pharmacologically            acceptable cations (e.g., sodium salt). Alternatively, several preferred      examples such as spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,5'-thiazolidine    )-2',4'-dione and related examples which contain a basic nitrogen in          ring(s) A and/or B according to Formula I can be formulated as the acid       salt with pharmacologically acceptable strong acids (e.g., hydrochloride  

The novel compounds of the present invention are readily prepared fromappropriate ketones of Formula II of their methylene analogs of FormulaIII: ##STR22## wherein A and B are previously defined with the exceptionthat introduction of a nitro substituent(s) is conducted after hydantoinderivatization. Similarly, certain other derivatizations, e.g.,esterification of carboxylic acids, oxidation of alkyl sulfides tosulfoxides or sulfones and direct aromatic halogenations may beconveniently performed after the tricyclic aromatic is spiro-imidederivatized, e.g., converted to the hydantoin or thiazolidinedione. Inaddition, certain labile protecting groups may be employed as is knownand practiced in the art.

The four major derivatization methods to transform tricycles of FormulasII and III into derivatives of Formula I follow.

METHOD I--SPIRO-TRICYCLICIMIDAZOLIDINEDIONES (HYDANTOIN DERIVATIZATION)

The novel spiro-hydantoin derivatives of the present invention arereadily prepared from appropriate ketones of Formula II, wherein A and Bare previously defined. For example, spiro-imidazolidinedionederivatives (29) and (41) are prepared respectively from5H-indeno[1,2-b]pyridin-5-one and 9H-pyrrolo[1,2-a]indolin-9-one:##STR23##

Similarly, spiro-imidazolidinedione derivative (39) is prepared from itsstarting material ketone 8H-indeno[2,1-b]thiophen-8-one: ##STR24## Tosynthesize a spiro-imidazolidinedione derivative, the ketone in FormulaII is condensed with an alkali metal cyanide, such as potassium cyanide,and ammonium carbonate. The reaction is typically conducted in thepresence of a ketone solubilizing inert polar organic solvent whichinclude, but is not limited to, water miscible alcohols such as ethanoland isopropanol, lower alkylene glycols such as ethylene glycol andtrimethylene glycol, N,N-di(lower alkyl), lower alkanoamides such asN,N-dimethyl-formamide, acetamide. In general, the reaction is conductedat temperatures ranging from 60° C. to about 180° C. (preferably 100° C.to 130° C.) for 6 hours to about 4 days, depending upon the ketone,solvent and temperature used. In general reagents in this reaction areemployed in excess of stoichiometric amounts to provide maximumconversion of the ketone substrate to the spirohydantoin derivative. Forexample, a moderate excess of potassium cyanide (i.e., 1.1 equiv) and a1.5 to 4 fold excess of ammonium carbonate achieves an increased yieldof spirohydantoin derivative based upon ketone starting material.Reaction ketone substrates of Formula II are prepared by methods knownto those skilled in the art. Typical preparative methods for substrateketones are represented by, but are not limited to, examples in Table Aand in the example preparations which follow.

METHOD II--SPIRO-TRICYCLICTHIAZOLIDINEDIONES

The novel spiro-tricyclicthiazolidinedione derivatives of the presentinvention are readily prepared from appropriate fluorene andheterocyclic analogs of fluorene derivatives of Formula III, wherein Aand B are previously defined. For example, spiro-thiazolidinedionederivative (26) is prepared from 5H-indeno[1,2-b]pyridine: ##STR25##Likewise, the spiro-thiazolidinedione of example (12) is prepared fromits starting material 2-fluoro-9H-fluorene: ##STR26## The synthesis of aspiro-thiazolidinedione from the corresponding tricyclic fluorene orheterocyclic fluorene derivative is a multistepped synthesis as depictedin Example IV. The first step involves metalation with a lower alkyllithium reagent such as n-butyllithium in an inert aprotic solvent suchas diethyl ether or tetrahydrofuran under an inert atmosphere ofnitrogen or argon, e.g., metalation of 2-fluoro-9H-fluorene: ##STR27##Metalation occurs primarily at the methylene bridge. Reaction withcarbon dioxide results in carbonation of the bridge carbon to yield uponisolation the carboxylic acid, e.g., 2-fluoro-9H-fluoren-9-carboxylicacid: ##STR28## Isolation of the carboxylic acid derivative can beaccomplished by a process including acidification, simple columnchromatography and solvent recrystallization similar to the processcited in Example IV. In contrast to this general case, metalation andcarbonation of 8H-indeno[1,2-c] thiophene results in a significantformation of 8H-indeno[1,2-c] thiophene-1-carboxylic acid and8H-indeno[1,2-c] thiophene-3-carboxylic acid in addition to the desired8H-indeno [1,2-c] thiophene-8-carboxylic acid, MacDowell and Jefferies;J. Org. Chem., 35 (1970) 871. The tricyclic carboxylic acid product isthen esterified with a lower alkylalcohol such as methanol in thepresence of an acid catalyst such as a hydrogen halide, such ashydrochloric acid. In a typical procedure, the acid (e.g.,2-fluoro-9H-fluorene-9-carboxylic acid) is esterified by the addition ofacetyl chloride to methanolic solution of the carboxylic acid withreflux: ##STR29## Proton abstraction from the acidic methine bridge ofthe carboxylic ester by an alkali alkoxide such as sodium metal inmethanol or alkali hydride such as potassium hydride in DMSO or DMFgenerates a carbanion. Introduction of purified dry oxygen results inoxidation of the methine carbon. Bisulfite reduction and a simplework-up involving filtration results in the isolation of an α-hydroxyester product, e.g., 2-fluoro-9-hydroxy-9H-fluoren-9-carboxylic acidmethyl ester: ##STR30## α-Halogenation of the α-hydroxy ester by athionyl halide such as thionyl chloride at reflux transforms2-fluoro-9-hydroxy-9H-fluoren-9-carboxylic acid methyl ester into9-chloro-2-fluoro-9H-fluoren-9-carboxylic acid methyl ester: ##STR31##

In a typical work-up procedure the cooled reaction mixture is dilutedwith benzene or a similar inert solvent, as known to those skilled inthe art, and the solution is evaporated with reduced pressure and heatto yield the α-halo ester. The α-halo ester, e.g.,9-chloro-2-fluoro-9H-fluoren-9-carboxylic acid methyl ester, is reactedwith thiourea in an anhydrous polar high boiling relatively nonbasicsolvent such as dioxane at reflux for 6-24 hours. Work-up and simplechromatography as is known to those skilled in the art results in theisolation of a spiro-tricyclicaminothiazolone product, e.g.,spiro-[2-fluoro-9H-fluoren-9,5'-(2'-amino-4'-thiazolone]: ##STR32##Hydrolysis of the spiro-aminothiazolone in an acidic aqueous alcoholicsolution such as concentrated hydrochloric acid in methanol yields thespiro-thiazolidinedione, e.g.,spiro-(2-fluoro-9H-fluorene-9,5'-thiazolidine)-2',4'-dione. ##STR33##

Reaction starting materials, tricyclic fluorene and tricyclicheterocyclic flourene derivatives of Formula III, are prepared bymethods known to those skilled in the art. Typical preparative methodsare represented by, but are not limited to, preparation examples ofTable A and in the examples which later follow.

METHOD III--SPIRO-TRICYCLICOXAZOLIDINEDIONES

The novel spiro-tricyclic-oxazolidinedione derivatives of the presentinvention are readily prepared from appropriate derivatives of floureneand heterotricyclic analogs of fluorene of Formula III, wherein A and Bare previously defined. The synthesis of the spiro-oxazolidinediones andspiro-thiazolidinediones (see II) generally have common syntheticintermediates. For example, spiro-tricyclicoxazolidinedione derivative(6) is prepared from the tricyclic α-hydroxy ester,2-fluoro-9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester, which isan intermediate in the synthesis of spiro-tricyclic-thiazolidinedione(12). Reaction of the α-hydroxy ester with 1 to 2 (preferably 1.1)equivalents of urea and 1 to 2 (preferably 1.05) equivalents of analkali alkoxide in a lower alkyl alcohol at reflux such as sodiumethoxide in ethanol yields the spiro-tricyclic-oxazolidinedione. Theisolation procedure involves the addition of water to the reaction,acidification with a mineral acid such as hydrochloric acid, simplefiltration and column chromatography. Such common product isolationprocedures are well known to those skilled in the art. The isolatedproduct, in this example, isspiro-(2-fluoro-9H-fluorene-9,5'-oxazolidinedione)-2',4'-dione.Similarly, other tricyclic α-hydroxy esters known in the art are derivedfrom the appropriate fluorene derivatives and heterotricyclic analogs offluorene derivatives, as are represented in but not limited by thoseexamples cited in Table A and in the following example preparations, canbe utilized to prepare spiro-tricyclicoxazolidinediones according tothis general scheme: ##STR34##

METHOD IV--SPIRO-TRICYCLICSUCCINIMIDES

The novel spiro-tricyclicsuccinimide derivatives of the instantinvention are readily prepared from appropriate fluorene derivatives andheterocyclic analogs of fluorene of Formula III, wherein A and B arepreviously defined. The synthesis of the spiro-tricyclicsuccinimides,spiro-oxazolidinediones and spiro-thiazolidinediones generally havecommon synthetic intermediates. For example, spiro-tricyclicsuccinimidederivatives (20) and (21) are prepared from the tricyclic acid esters,9H-fluorene-9-carboxylic acid methyl ester and2-fluoro-9H-fluorene-9-carboxylic acid methyl ester respectively whichare intermediates in the synthesis of spiro-tricyclicthiazolidinediones(9) and (12) and spiro-tricyclicoxazolidinediones (2) and (6). Reactionof the carboxylic alkyl ester with 1 to 1.5 equivalents (preferably 1.1)of an alkali metal alkoxide such as sodium methoxide in an alkyl alcoholsuch as methanol followed by reaction with 1-2 equivalents (preferably1.1) of 2-haloacetamide such as 2-chloroacetamide (Aldrich Chemical,Inc.) at 10° to 50° C. (preferably ambient temperature) under an inertatmosphere such as nitrogen for a period of 8 hrs. to 4 days dependingupon temperature, haloacetamide reagent and solvent employed. Typicalreaction times with methanol solvent, chloroacetamide reagent at roomtemperature can be 48 hrs. The reacted mixture is typically poured into1-4X volume of 1-5% alkali hydroxide such as 2.5% sodium hydroxide.Insolubles are removed by filtration. The filtrate is acidified with adilute or concentrated mineral acid such as concentrated hydrochloricacid and the resulting precipitate is collected by filtration with coldwater wash. Solvent recrystallizations may be employed as is known inthe art to further purify the resulting spiro-tricyclicsuccinimideproduct. Specifically, 9H-fluorene-9-carboxylic acid methyl ester and2-fluoro-9H-fluorene- 9-carboxylic acid methyl ester yield respectively,after the above treatment, spiro-(9H-fluorene-9,3'-succinimide) andspiro-(2-fluoro-9H-fluorene-9,3'-succinimide).

Similarly, other tricycliccarboxylic acid esters known in the art arederived from the fluorene derivatives and heterotricyclic analogs offluorene and derivatives, as are represented in but not limited to thoseexamples cited in Table A and in the following example preparations canbe utilized to prepare spiro-tricyclicsuccinimides according to thisgeneral scheme: ##STR35##

METHOD V--HALOGENATION AND DERIVATIZATION OF FLUORENE, FLUORENONE ANDTHEIR INDENO-HETEROCYCLE ANALOGS AND DERIVATIVES

Halogenation of fluorene and fluorenone and related indeno heterocycleanalogs such as 4-azafluorene or 4-azafluorenone and as exampled inTable A where Q is dihydrogen and oxygen can be accomplished by methodsknown and practiced in the art (e.g., Eckert and Langecker, J. Prakt.Chem., 118, 263 (1928); Courot, Ann. Chem., 14, 5 (1930); Bell andMulholland, J. Chem. Soc., 2020 (1949); Johnson and Klassen, J. Chem.Soc., 988 (1962)). In general, chlorination of fluorenone and fluorenederivatives and related heterocyclic indeno analogs is accomplished bydissolving the substrate in glacial acetic acid containing anhydrousferric chloride (10-20% by weight of substrate) and chlorine gas orchlorine dissolved in glacial acetic acid (1.2 to 3.0 molar equiv.) isadded. The reaction is stirred at a selected temperature for severalhours and allowed to cool; the crude product is isolated and solventrecrystallized to yield the chlorinated derivative.

The structure-reactivity of tricyclic azines, nitrogen analogs offluorenone and fluorene, to electrophillic halogenation has beencharacterized by Mlochowski and Szulc, J. Prakt. Chem., 322 (1980) 971.

Fluorination of selected derivatives of fluorene (and fluorenone) andindeno heterocyclic analogs involves a multistepped process wherein thesubstrate is first nitrated (Kretor and Litvinov, Zh. Obsch. Khim., 31,2585 (1961); Org. Syntheses, Coll. Vol. II, 447 (1943); Org. Syntheses,Coll. Vol. V, 30 (1973)). The resulting nitro derivative is reduced viaRaney nickel and hydrazine, zinc dust and calcium chloride, iron filingsand concentrated hydrochloride acid, palladium on carbon with hydrazineand other methods known to the art (Org. Syntheses Coll. Vol. II, 447(1943); Org. Syntheses Coll. Vol. V, 30 (1973); Fletcher and Namkung, J.Org. Chem., 23, 680 (1958)). The resulting aromatic amine(s): (a) issubjected to the Schiemann reaction according to the method of Fletcherand Namkung, Chem. and Ind., 1961, 179, wherein the ammoniumfluoroborate salt, prepared in the presence of tetrahydrofuran is firstdiazotized and then decomposed in hot xylene to yield the correspondingfluoro derivative. Oxidation of the fluoro derivative, e.g.,2-fluoro-9H-flourene, according to Sprinzak, J. Amer. Chem. Soc., 80,5449 (1958) or by other oxidation procedures known and practiced in theart, yields the ketone, e.g., 2-fluoro-9H-fluoren-9-one. In a generaland novel process cited in U.S. Pat. Nos. 4,438,272 and 4,436,745, thefluorinated ketone is converted into the corresponding alkylsulfide,alkysulfoxide and/or alkylsulfone. An alkaline metal alkysulfidenucleophile (e.g., sodium methylthiolate in DMF) displaces fluoride toyield the corresponding alkylsulfide derivative, e.g.,2-methyl-thiol-9H-fluoren-9-one. The resulting alkylsulfide derivativecan be oxidized by known procedures (e.g., sodium metaperiodate orhydrogen peroxide) to the corresponding sulfoxide and/or sulfone; (b) ashydrogen halide salt(s) is diazotized by sodium nitrate. Replacement ofthe diazonium group(s) in these aromatic derivatives by a halo or cyanogroup(s) (e.g., via KNC) salts (Sandmeyer), copper powder (Gatterman) orcupric salts (Korner-Contardi). See Organic Synthesis Vol. I, p. 170(1932); E. Pfeil, Angew. Chem., 65, 155 (1953); Y. Nakatani, TetrahedronLett., 1970, 4455. As is known in the art, the resulting cyanoderivatives can be hydrolyzed into carboxylic acids; alcoholyzed tocarboalkoxy esters, e.g., carboethoxy esters; hydrolyzed to carboxamide;reduced to methylamine, etc., as is well known and practiced in the art.Other aromatic derivatizations can similarly be made by those skilled inthe art. According to a general process of Teulin et al., J. Med. Chem.,21 (1978) 901, tricyclic indeno derivatives with the general formula:##STR36## (where B is a previously defined) are derivatized to thecorresponding arylisopropanoic and arylacetic acids. The processinvolves the following synthetic steps: ##STR37## In accordance withMethod VII the aforementioned indeno derivatives can be oxidized to thecorresponding ketones which are starting material substrates forspiro-hydantoin derivatization in accordance with Method I.

A serial process involving several of the aformentioned processes can beemployed to introduce for example a fluoro, and a chloro substituentinto the same tricyclcic-aromatic substrate. Other fluorene andfluorenone derivatives and indeno heterocyclic analog derivatives can beprepared in accordance with common synthetic procedures known andpracticed in the art.

Finally, tricyclic aromatic azine derivative such as 5H-indeno[1,2b]pyridine-5-one or 5H-indeno[1,2-b]pyridine, can be pyridine N-oxidizedto yield the corresponding pyridine N-oxide derivative. Such an N-oxideis employed to prepare the corresponding spiro-hydantoin derivativeaccording to Method I or spiro-oxazolidinedione and spiro-succinimideaccording to Methods III and IV respectively. For example, ##STR38##

METHOD VI

The novel spiro-tricyclic-imidazolidinediones, -thiazolidinediones,-oxazolidinediones and -succinimides may be further derivatizedaccording to the following.

Nitrated fluorenone will not easily derivatize to form the correspondingspiro-hydantoin.

The preferred method of preparation of spiro-hydantoin aromatic nitroderivatives is via direct nitration (e.g., via nitric acid and 60%sulfuric acid) of the spiro-cyclic derivatives, especiallyspiro-hydantoin (see Example XI). After nitration of the selectedspiro-tricyclic-imidazolidinediones, -thiazolidinediones,-oxazolidinediones and succinimides by methods well known and practicedin the art, the corresponding aromatic nitro group(s) of correspondingspiro-tricyclic derivative(s) of the present invention can be reduced tothe corresponding amine derivative(s). Aromatic nitro group(s) reductionto the aromatic amime(s) can be accomplished by a number of methodsincluding reduction by hydrazine hydrate and Raney Nickel (see Fletcherand Namkung, J. Org. Chem., 23, 680 (1958). The resulting amine(s) ashydrogen halide salt(s) is diazotized by sodium nitrite. Replacement ofthe diazonium group(s) in these aromatic derivatives by a halo or cyanogroup(s) (e.g., via KCN) salts (Sandmeyer), copper powder (Gatterman) orcupric salts (Korner-Contardi). See Organic Synthesis Vol. I. p. 170(1932); E. Pfeil, Angew. Chem., 65, 155 (1953); Y. Nakatani, TetrahedronLett., 1970, 4455. As is known in the art, the resulting cyanoderivatives can be hydrolyzed into carboxylic acids; alcoholyzed tocarboalkoxy esters, e.g., carboethoxy esters; hydrolyzed to carboxamide;reduced to methylamine, etc., as is well known and practiced in the art.Other aromatic derivatizations can similarly be made by those skilled inthe art.

Spiro-tricyclic azine derivative, such as spiro-(7-fluoro-5H-indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione, is oxidized to thecorresponding N-oxide derivative according to the general procedure ofMosher et al., Org. Syn., 33 (1953) 79 wherein peracetic acid isemployed as the oxidizer. Such an N-oxide is active as aldose reductaseinhibitor. For example, ##STR39##

METHOD VII

Heterocyclic analogues of fluorene and fluorene derivatives such as1-azafluorene and 2-fluoroflourene can be transformed into correspondingketones (e.g., 1-azafluorenone or 2-fluorofluorenone) via a number ofoxidation procedures which are well known to those skilled in the art.Some relevant representative methods include:

a) Oxidation by oxygen under basic conditions according to a generalprocedure of U. Sprinzak, J. Amer. Chem. Soc., 80 (1958) 5449.

b) Oxidation by permanganate in which the flourene derivative isoxidized by potassium permanganate in acetone, e.g., see Urbina,Synthetic Communications 9 (1979), 245.

c) Oxidation by selenium dioxide in a sealed vessel at 200°-250° C. whencommon oxidation procedures such as chromuim trioxide in acetic acid areineffective. See Arcus and Barnett, J. Chem. Soc. (1960) 2098.

METHOD VIII

Tricyclic ketones of the present invention may be reduced to thecorresponding methylene reduction product by the Wolff-Kishner Reductionor by the Huang-Minlon modified Wolff-Kishner Reduction (see alsoMacDowell and Jefferies, J. Org. Chem., 35, 871 (1970)). Alternatively,these ketones may be reduced by lithium aluminum hydride in the presenceof aluminum chloride (see Rault, Lancelot and Effi, Heterocycles 20, 477(1983)) or by other reduction methods known to those skilled in the art.

METHOD OF TREATMENT IX

The spiro-tricyclic-thiazolidinedione, -imidazolidinedione,-oxazolidinedione and -succinimide compounds of the present inventionare weak acids. In addition, several examples, as cited in Example XIX,are carboxylic acid derivatives and/or aromatic azines (i.e., contain abasic nitrogen(s) in the aromatic tricycle) and/or contain an alkylaminesubstituent. Therefore, these compounds are ameanble to preparation asbase salts and in some cases, where basic amines are present, acidsalts. Several examples contain both an acidic spiro functionality andcarboxylic acid functionality. These cases can be prepared as mono- ordi-basic salts.

The chemical bases which are used as reagents to prepare theaforementioned pharmaceutically acceptable base salts are those whichform nontoxic (pharmaceutically acceptable) salts with the variousherein described acidic spiro-imidazolidinedione, -thiazolidine-dione,-oxazolidinedione and -succinimdie derivatives such asspiro-(7-fluoro-5-H-indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione, for example. Similarly, hereindescribed carboxylic acid containing derivatives, such asspiro-(2-carboxy-9H-fluoren-9,5'-thiazolidine)-2',4'-dione, can beprepared as nontoxic salts. These nontoxic base salts are of a naturenot to be considered clinically toxic over a wide therapeutic doserange. Examples of such cations include those of sodium, potassium,calcium, magnesium, etc. These pharmacologically acceptable nontoxicsalts can be prepared by treating the aforementioned acidic specie,e.g., spiro-thiazolidinedione, with aqueous metallic hydroxide solution,and then evaporating the resulting solution, preferably at reducedpressure, to dryness. Alternatively, where indicated, the base salts canbe prepared by mixing a lower alkanolic solution (e.g., ethanol) of theacidic compound with a desired alkali metal alkoxide (e.g., sodiumethoxide) in a lower alkanolic solution, and evaporating the solution todryness in the same manner as before. In any case stoichiometricquantities of reagents must be employed in order to ensure completenessof reaction and maximum production of yields with respect to the finalbase salt product.

Acid salts of spiro-tricyclic azine derivatives, e.g.,spiro-(7-fluoro-5H-indeno[1,2-b]pyridine-5,5'-thiazolidine)-2',4'-dione,can be prepared with nontoxic pharmacologically acceptable acids, e.g.,hydrochloric acid and sulfuric acid. Examples of such anions of saidacid salts include those of hydrogensulfate, sulfate, chloride, etc.These pharmacologically acceptable nontoxic acid salts can be preparedby treating the aforementioned basic specie, e.g., spiro-azafluorenederivative, with an acidic aqueous solution of the desired acid. Afterthe basic species is solubilized in the acid, the solution is evaporatedto dryness, preferably with reduced pressure. In this case,stoichiometric quantities of acid are preferred. Alternatively, in somecases the acid salt may be precipitated or recrystallized from strongacid solution (e.g., 5% hydrochloric acid). The salt then is collectedby filtration and dried.

As previously indicated, the spiro-tricyclic-thiazolidinedione,-imidazolidinedione, -oxazolidinedione and -succinimide compounds ofthis invention are all readily adapted to therapeutic use as aldosereductase inhibitors for the control of chronic diabetic complications,in view of their ability to reduce lens sorbitol levels in diabeticsubjects to a statistically significant degree. The herein describedcompounds of this invention can be administered by either the oral orparenteral routes of administration. In general, these compounds areordinarily administered in dosages ranging from about 0.1 mg to about 10mg/kg of body weight per day, although variations will necessarily occurdepending upon the weight and condition of the subject being treated andthe particular route of administration chosen; the preferred range is0.5 to 4.0 mg/kg. Oral administration is preferred.

While matters of administration are left to the routine discretion ofthe clinician, long term, prophylactic administration of the compoundsof the present invention is generally indicated on diagnosis of diabetesmellitus and/or neuropathy and/or retinopathy and/or vasculopathy and/orcataract and/or impaired wound healing and/or nephropathy and/orhyperglyceamia.

In connection with the use of the spiro-tricycle compounds of thisinvention for the treatment of diabetic subjects, it is to be noted thatthese compounds may be administered either alone or in combination withpharmaceutically acceptable carriers by either of the routes previouslyindicated, and that such administration can be carried out in bothsingle and multiple dosages. More particularly, the compounds of thisinvention can be administered in a wide variety of different dosageforms, i.e., they may be combined with various pharmaceuticallyacceptable inert carriers in the form of tablets, capsules, lozenges,troches, hard candies, powders, sprays, aqueous suspensions, injectablesolutions, elixirs, syrups, and the like. Such carriers include soliddiluents of fillers, sterile aqueous media and various nontoxic organicsolvent, etc. Moreover, such oral pharmaceutical formulations may besuitably sweetened and/or flavored by means of various agents of thetype commonly employed for just such purposes. In general, thetherapeutically useful compounds of this invention are present in suchdosage forms at concentration levels ranging from about 0.5% to about90% by weight of the total composition i.e., in amounts which aresufficient to provide the desired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in this connectionwould also include lactose or milk sugar as well as high molecularweight polyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter of dyes, and if so desired, emulsifying and/or suspending agentsas well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particularspiro-tricycles in sesame or peanut oil or in aqueous propylene glycolmay be employed, as well as sterile aqueous solutions of thecorresponding water-soluble, alkali metal or alkaline-earth metal oracid salts previously enumerated. Such aqueous solutions should besuitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. These particular aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. In this connection,the sterile aqueous media employed are all readily obtainable bystandard techniques well-known to those skilled in the art.Additionally, it also is possible to administer the aforesaidspiro-tricycle compounds topically via an appropriate ophthalmicsolution suitable for the present purposes at hand, which can then begiven dropwise to the eye.

The activity of the compounds of the present invention, as agents forthe control of chronic diabetic complications, is determined by theirability to successfully pass one or more of the following standardbiological and/or pharmacological tests, viz., (1) measuring theirability to inhibit the enzyme activity of isolated human aldosereductase; (2) measuring their ability to reduce or inhibit enzymeactivity of rat lens aldose reductase in vitro; (3) measuring theirability to preserve motor nerve conduction velocity in chronicstreptozotocin-induced diabetic rats; (4) and measuring their ability todelay cataract formation and reduce the severity of lens opacities inchronic galactosemic rats; (5) measuring with electron microscopy theirability to prevent basement membrane thickening in the kidney glomerulusand/or retina capillaries in chronic streptozotocin-induced diabeticrats (6) measuring their ability to maintain rat lenses in 30 mM xyloseculture for 18 h.

Typical preparative methods and synthetic design for substituted analogsof the tricycles of Table A and Formulas II and III are provided forinstruction.

x, y and z are as previously defined. Where Q=H₂ or O

                  TABLE A                                                         ______________________________________                                        Substrates and Derivatives                                                                          Method of Preparation                                   ______________________________________                                         ##STR40##            A                                                        ##STR41##            B                                                        ##STR42##            C                                                        ##STR43##            D                                                        ##STR44##            E                                                        ##STR45##            E                                                        ##STR46##            E                                                        ##STR47##            E                                                        ##STR48##            E                                                        ##STR49##            F                                                        ##STR50##            G                                                        ##STR51##            H                                                        ##STR52##            I                                                        ##STR53##            J                                                        ##STR54##            J                                                        ##STR55##            J                                                        ##STR56##            J                                                        ##STR57##            J                                                        ##STR58##            K                                                        ##STR59##            L                                                        ##STR60##            M                                                        ##STR61##            N                                                        ##STR62##            O                                                        ##STR63##            O                                                        ##STR64##            P                                                        ##STR65##            P                                                        ##STR66##            P                                                        ##STR67##            P                                                        ##STR68##            P                                                        ##STR69##            P                                                        ##STR70##            Q                                                       ______________________________________                                    

PREPARATION A

Synthesis substrates 8H-indeno[2,1-b]thiophen-8-one and 8H-indeno[2,1-b]thiophene and their derivatives are prepared in accordance withthe following by a general method of Venin, Brault and Kerfanto, C. R.Acad. Sc. Paris, 266 (c), 1650 (1968), various substitutedphenylglyoxals are prepared in a three step process involving: gemdibromination of the substituted acetophenone (e.g.,p-fluoroacetophenone) to the corresponding α, α-dibromoacetophenone;nucleophillic displacement of the gem bromides to yield thecorresponding animal; aqueous acid (e.g., dilute HCl) hydrolysis toyield the substituted phenylgloxal, e.g., p-fluorophenylglyoxal. By sucha process the following substituted phenylglyoxals are prepared:##STR71## X and Y=H, halogen, lower alkyl, lower cycloalkyl, COOH,C.tbd.N, --O--R, --S--R, --S(O)R, --SO₂ R

R=Lower alkyl

from commercially available substituted acetophenones (e.g., o-, p-or m-fluoro- chloro- or bromo - acetophenone may be purchased from AldrichChemical, Inc.). Other substituted acetophenones are prepared by methodswell known to those skilled in the art. Phenglyoxal (Aldrich Chemical,Inc.) is commercially available. Such prepared substitutedphenylglyoxals (e.g., 4'-fluorophenylglyoxal) are utilized to synthesizecorresponding substituted 8H-indeno[2,1-b]thiophen-8-one and8H-indeno[2,1-b]thiophene substrates which are derivatized by MethodsI-IV. The synthesis of substituted 8H-indeno[2,1-b]thiophen-8-oneinvolves the Hinsberg Stobbe type condensation (Wolf and Folkers, Org.Reactions, 6, 410 (1951)) between the substituted phenylglyoxal, e.g.,4'-fluorophenylglyoxal, and diethylthiodiglycolate using sodiumethoxide. After saponification, the isolated substituted3-phenyl-2,5-thiophenedicarboxylic acid, e.g.,3-(4'-fluorophenyl)-2,5-thiophenedicarboxylic acid is treated withthionyl chloride to form the diacylchloride which is intramolecularlycyclized by a Friedel-Crafts reaction catalyzed by aluminum chloride orstannic chloride to give the correspondingly substituted8-oxo-8H-indeno-[2,1-b]thiophen-2-carboxylic acid, e.g.,6-fluoro-8-oxo-8H-indeno-[2,1-b]thiophen-2-carboxylic acid, (A-1), whichcan be converted into a hydantoin derivative according to Method I.Decarboxylation of (A-1) by copper powder in anhydrous quinoline yieldsthe corresponding substituted 8H-indeno-[2,1-b]thiophen-8-one (A-2)which is converted (in accordance with Method I) into a hydantoinderivative such asspiro(6-fluoro-8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione.See Example XIV for the preparation ofspiro-(8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione. TheWolff-Kishner reduction (Method VIII) of (A-1) or (A-2), preferably(A-1), yields the corresponding substituted 8H-indeno[2,1-b]thiophene,e.g., 6-fluoro-8H-indeno-[2,1-b]thiophene. In the alkaline hydrazine (inexcess) reduction of the ketoacid (A-l), both keto reduction anddecarboxylation may occur. Product isolation is best accomplished byfractional distillation, but may involve other separation methods as areknown in the art. Further derivatization may be accomplished accordingto Method V. The resulting substituted 8H-indeno[2,1-b]thiophene ismetalated by n-butyllithium and carbonated in the methylene bridge toyield the corresponding 8-carboxylic acid which, after esterification,at reflux with a lower alkyl alcohol such as methanol under acidcatalyzed conditions such as concentrated hydrochloric acid yields thecorresponding substituted or unsubstituted 8H-indeno[2,1-b]thiophen-8-carboxylic acid alkyl ester, e.g.,6-fluoro-8H-indeno[2,1-b]thiophen-8-carboxylic acid methyl ester. Theester is utilized according to Methods II, III and IV to yield thecorresponding spiro-thiazolidinedione, spiro-oxazolidine-dione andspiro-succinimide such asspiro-(6-fluoro-8H-indeno[2,1-b]thiophen-8,5'-thiazolidine)-2',4'-dione,spiro-(6-fluoro-8H-indeno-8,5'-oxazolidine)-2,4'-dione andspiro-(6-fluoro-8H-indeno[2,1-b]thiophen-8,3'-succinimide) respectively.

PREPARATION B

Synthesis substrates 4H-indeno[1,2-b]thiophen-4-one and 4H-indeno[1,2-b]thiophene can be prepared according to a general process ofMacDowell and Jefferies, J. Org. Chem., 35, 871 (1970). In this processthe 4-one substrate is prepared by the Ullmann coupling of ortho-iodo orortho-bromo, di, tri and tetrasubstituted benzoic acid lower alkylesters, such as 3-fluoro-2-iodo-benzoic acid ethyl or methyl ester(Chem. Abst.; 27:1339/G) or 2-bromo-4-fluoro-benzoic acid methyl ester(Chem. Abst. 99(1):5630j) or 2-bromo-5-chlorobenzoic acid methyl ester(J. Med. Chem., 13, 567-8 (1970) with 2-iodo or 2-bromothiophene(Aldrich Chemical, Inc.). Saponification of the coupled product willyield the corresponding substituted 2-(2'-thienyl) benzoic acid (e.g.,5-chloro-2-(2'-thienyl)benzoic acid from 2-bromo-5-chloro-benzoic acidmethyl ester). Cyclization of the acid is performed via the aroyl halideusing stannic chloride or aluminum chloride to yield to substituted 4H-indeno[1,2-b]thiophen-4-one (B-1) (e.g.,6-chloro-4H-indeno[1,2-b]thiophen-4-one). This 4-one derivative isconverted (in accordance with Method I) into a hydantoin derivative suchasspiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione.See Example XIII for the preparation ofspiro-(4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione. TheWolff-Kishner reduction (Method VIII) of (B-1) yields the corresponding4H-indeno[1,2-b]thiophene. Product isolation is best accomplished byfractional distillation, but may involve other separation methods as areknown in the art. The resulting substituted or unsubstituted4H-indeno[1,2-b]thiophene (which may be further derivatized according toMethod V) is metalated by n-butyllithium and carbonated in the methylenebridge to yield the corresponding 4-carboxylic acid which afteresterification at reflux with a lower alkyl alcohol such as methanolunder acid catalyzed conditions such as concentrated hydrochloric acidyields the corresponding substituted or unsubstituted4H-indeno[1,2-b]thiophen-4-carboxylic acid lower alkyl ester, e.g.,6-chloro-4H-indeno[1,2-b]thiophen-4-carboxylic acid methyl ester. Theester is utilized according to Methods II, III, and IV to yield thecorresponding spirothiazolidinedione, spiro-oxazolidinedione andspiro-succinimide such asspiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,5'-thiazolidine]-2',4'-dione,spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,5'-oxazolidine)-2',4'-dioneand spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,3'-succinimide)respectively. The resulting spiro-derivatives may be further derivatizedaccording to Method VI.

PREPARATION C

Synthesis substrates 4H-indeno[1,2-c]thiophen-4-one and 4H-indeno[1,2-c]thiophene and their derivatives are prepared in accordance withMacDowell and Jefferies, J. Org. Chem., 35, 871 (1970). Whereintreatment of 4-bromo-3-thienyllithium with a commonly available loweralkyl substituted cyclohexanone or cyclohexanone, such as4-methylcyclohexanone, at -65° to -75° C. yields the correspondingcyclohexanol derivative which is dehydrated with para-toluenesulfonicacid in refluxing benzene or toluene to yield a cyclohexylthiopheneproduct such as 3-bromo-4-(4-methyl-1'-cyclohexenyl)thiophene.Dehydrogenation with tetrachlorobenzoquinone in refluxing xylene for8-24 hours yields the corresponding 3-bromo-4-phenylthiophene, e.g.,3-bromo-4-(4'-methylphenyl)thiophene. After purification by sublimationand/or chromatography over alumina, the bromide is subjected tohalogen-metal exchange at -65° to -75° C. with n-butyllithium in ether,followed by carbonation with carbon dioxide. The isolated3-phenyl-thiophene-4-carboxylic acid derivative, e.g.,3-(4'-methylphenyl)thiophene-4-carboxylic acid, is converted withthionyl chloride to the acid halide. Ring closure to the ketone viaheating the aroyl chloride and aluminum chloride in carbon disulfide for18-36 hours yields the corresponding ketone, such as6-methyl-8H-indeno[1,2 -c]thiophen-8-one. This 8-one derivative, whichmay be further derivatized according to Method V, is converted (inaccordance with Method I) into a hydantoin derivative. Wolff-Kishnerreduction (Method VIII) of the 8-one derivative (and optionalderivatization according to Method V) and spiro-derivatization inaccordance with Methods II, III and IV yields the correspondingspiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimidederivatives respectively. These spiro-derivatives may be furtherderivatized according to Method VI.

PREPARATION D

Synthesis substrate 7H-cyclopenta[1,2-b:4,3-b']dithiophene is preparedaccording to the method of Wynberg and Kraak, J. Org. Chem., 29, 2455(1964). The corresponding spiro-thiazolidinedione,spiro-oxazolidinedione and spiro-succinimide derivatives are preparedaccording to Methods II-IV respectively. The 7-one derivative isprepared from the cyclopentadithiophene in accordance with the oxidationprocedures cited in Method VII. The ketone, 7H-cyclopenta[1,2-b:4,3-b]dithiophen-7-one is converted into the spiro-hydantoinderivative in accordance with Method I.

PREPARATION E

Synthesis substrates4H-cyclopenta[2,1-b:3,4-b']dithiophene,7H-cyclopenta[1,2-b:3,4-b']dithiophene,7H-cyclopenta[1,2-c:3,4-c']dithiophene,7H-cyclopenta[1,2-b:3,4-c']dithiophene and7H-cyclopenta[2,1-b:3,4-c']dithiophene are prepared according to theprocedure of Wiersema and Wynberg, Tetrahedron, 24, 3381 (1968). Fromthese, the corresponding spiro-thiazolidinedione, spiro-oxazolidinedioneand spiro-succinimide derivatives are prepared according to MethodsII-IV respectively. The corresponding4H-cyclopenta[2,1-b:3,4-b']dithiophen-4-one,7H-cyclopenta[1,2-b:3,4-b']dithiophen-7-one,7H-cyclopenta[1,2-c:3,4-c']dithiophen-7-one,7H-cyclopenta[1,2-b:3,4-c']dithiophen-7-one and7H-cyclopenta[2,1-b:3,4-c']dithiophen-7-one are prepared in accordancewith the oxidation procedures cited in Method VII. The resulting ketonesare spiro-hydantoin derivatized in accordance with Method I.

PREPARATION F

Synthesis substrates 5H-indeno[1,2-b]pyridin-5-one and5H-indeno[1,2-b]pyridine (as 4-azafluorene from Aldrich Chemical, Inc.)and their derivatives are prepared according to a general procedure ofParcell and Hauck, J. Org. Chem., 21, 3468 (1963), wherein thepiperidineenamine of 2,3-dihydro-1H-inden-1-one (available from AldrichChemical, Inc.), -4,-5 or -6-chloro or fluoro-2,3-dihydro-1H-inden-1-one(Olivier and Marechal, Bull. Soc. Chim. France, (1973), 3092),6-chloro-5-cyclopentylmethyl-2,3-dihydro-1H-inden-1-one (Biere et al.,Eur. J. Med., 18, 255 (1983)), 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one(Koo, J. Amer. Chem. Soc., 75, 1891 (1953)), 5 or6-methoxy-2,3-dihydro-1H-inden-1-one (available from Aldrich Chemical,Inc.) or other substituted 1-indanones is formed from piperidine in thepresence of p-toluensulfonic acid catalyst according to the procedure ofHeyl and Herr, J. Amer. Chem. Soc., 75, 1918 (1953). The resultingpiperidineenamine is reacted with 3-bromopropylamine hydrobromide orhydrochloride (available from Aldrich Chemical, Inc.) to yield an imineproduct.

The process typically involves the addition of 1.1 molar equivalents ofthe enamine to 1 molar equivalent of bromopropylamine hydrobromide indimethylformamide at elevated temperature until the exothermic reactionis initiated wherein the temperature is kept at 90°-120° C. for severalhours. The product is isolated by a combination of acidification andether washing followed by basification and ether extractions.Evaporation yields the tetrahydroimine product such as: ##STR72## Thetetrahydroimine product is aromatized in xylene and nitrobenzene and 10%palladium on charcoal according to Parcell and Hauch, ibid. Theresulting product, e.g., 7-fluoro-5H-indeno[1,2-b]pyridine (which may befurther derivatized according to Method V) is derivatized according toMethods II to IV to yield the corresponding spiro-derivatives such asspiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,5-thiazolidine)-2',4'-dione;spiro-(7-fluoro-5H-inden[1,2-b]pyridin-5,5'-(oxazolidine)-2',4'-dioneand spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,3'-suiccinimide. Oxidation(Method VII) of 5H-indeno[1,2-b]pyridine or its derivatives according tothe method of Sprinzak, J. Amer. Chem. Soc., 80, 5449 (1958) yields thecorresponding 5-one or ketone derivative, which may be furtherderivatized according to Method V. When reacted in accordance withMethod I, the ketone will yield a spiro-hydantoin derivative such asspiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione.Any of the aforementioned spiro derivatives may be further derivatized,e.g., nitrated, in accordance with Method VI. See Examples XVIII, XI andXII.

PREPARATION G

Synthesis substrates 5H-indeno[1,2-c]pyridin-5-one and5H-indeno[1,2-c]pyridine and their derivatives may be prepared inaccordance with the following. 3-Azafluorenone(5H-indeno[1,2-c]pyridine-5-one) is prepared according to the method ofMayor and Wentrup, J. Amer. Chem. Soc., 97, 7467 (1975). The ketone canbe derivatized in accordance with Method V. The ketone, e.g.,5H-indeno[1,2-c]pyridin-5-one, is hydantoin derivatized according toMethod I. A Wolff-Kishner reduction (Method VIII) of this3-azafluorenone can be accomplished according to Kloc et al.,Heterocycles 9, 849 (1978) to yield the corresponding5H-indeno[1,2-c]pyridine which is derivatized in accordance with MethodsII-IV to yield to the corresponding spiro-thiazolidinedione,spiro-oxazolidinedione and spiro-succinimide respectively. Theaforementioned spiro-derivatives may be further derivatized according toMethod VI.

PREPARATION H

Synthesis substrates 9H-indeno[2,1-c]pyridin-9-one and9H-indeno[2,1-c]pyridine are prepared according to the method of Mayorand Wentrup, J. Amer. Chem. Soc., 97, 7467 (1975). Furtherderivatization may be accomplished in accordance with Method V. Theresulting indenopyridine or 2-azafluorene product is further derivatizedaccording to Methods II-IV to yield the spiro-thiazolidinedione,spiro-oxazolidinedione and spiro-succinimide derivatives. Oxidation ofthe indenopyridine to the corresponding ketone is accomplished by sodiumdichromate or other oxidation procedures as cited in Table A. Theresulting ketone may be derivatized in accordance with Method V. Theselected 2-azafluoreneone derivative is derivatized to yield thespiro-hydantoin. See Example XVI for the preparation ofspiro-(9H-indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione. Theaforementioned spiro-derivatives may be further derivatized according toMethod VI.

Furthermore, in example, 7-amino-2-azafluorene or7-amino-9H-indeno[2,1-c]pyridine can be prepared according to the methodof Perin-Roussel and Jacquignon, C. R. Acad. Sc. Paris, 278, 279 (1974).This amino product, in accordance with Method V, can be transformed viathe Schiemann reaction into 7-fluoro-9H-indeno[2,1-c]pyridine. Thissubstrate, as above, can be transformed by Methods I-IV intospiro-(7-fluoro 9H-indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione,spiro-(7-fluoro9H-indeno[2,1-c]pyridin-9,5'-thiazolidinedione)-2',4'-dione,spiro-(7-fluoro 9H-indeno[2,1-c]pyridin-9,5'-oxazolidine)-2,4'-dione andspiro-(7-fluoro 9H-indeno[2,1-c]pyridin-9,3'-succinimide).

PREPARATION I

The ketone substrate, 9H-indeno[2,1-b]pyridin-9-one may be prepared bythe method of Kloc, Michowski and Szulc, J. prakt. chemie, 319, 95q(1977). This ketone can be derivatized according to Method V. Thesubstituted or unsubstituted ketone is then derivatized in accordancewith Method I to yield the spiro-hydantoin which may be further modifiedaccording to Method VI.

The ketone, from the above, is reduced to a method cited in Method VIIIor in general the Wolff-Kishner reduction to yield corresponding9H-indeno[2,1-b]pyridine which is then derivatized in accordance withMethods II, III and IV to yield spiro-thiazolidinedione,spiro-succinimide.

Alternatively, 5H-indeno[2,1-b]pyridine-5-one (also called1-azafluoren-9-one) and 5 to 8 position fluoro or chloro derivatives areprepared according to a general procedure of Urbina, Synthetic Comm., 9,245 (1979). Where to a substituted or unsubstituted 1-phenyl-2-propanone(e.g., 1-(4'-fluorophenyl)-2-propanone) is added acrylonitrile producinga corresponding 5-cyano-3-phenyl-2-pentanone, e.g.,5-cyano-3-(4'-fluorophenyl)-2-pentanone. The pentanone product ishydrogenated and cyclized to the corresponding2-methyl-3-phenylpiperidine, e.g.,2-methyl-3-(4'-fluorophenyl)piperidine. Aromatization of the2-methyl-3-phenyl piperidine is carried out in vapor phase with catalystK-16 (Prostakon, Mathew and Kurisher, Khim-Geterotsikl. Socd., 876(1970)) at 380° to 420° C. to yield the corresponding2-methyl-3-phenylpyridine. Alternatively, aromatization can be achievedwith Pd/C. Dehydrocyclization of the methyl-3-phenylpyridine at 500° to550° C. over K-16 will produce the appropriate 1-azafluorene, e.g.,7-fluoro-1-azafluorene. The 9H-indeno[2,1-b]pyridine and its derivatives(e.g., 7-fluoro-9H-indeno[2,1-b]pyridine) are converted in accordancewith Method II, III and IV into spiro-thiazolidinedione,spiro-oxazolidinedione and spiro-succinimide derivatives. The9H-indeno[2,1-b]pyridine is oxidized according to general procedurescited in Method VII or potassium permanganate (Urbina, ibid). Theresulting ketone, e.g., 7-fluoro-9H-indeno[2,1-b]pyridin-5-one, isderivatized in accordance with Method I to yield the spiro-hydantoinderivative, such asspiro-(7-fluoro-9H-indeno[2,1-b]pyridin-9,4'-imidazolidine)-2',5'-dione.

PREPARATION J

Synthetic substrates 5H-cyclopenta[2,1-b:4,3-b']dipyridin-5-one,5H-cyclopenta[1,2-b:3,4-c']dipyridin-5-one,5H-cyclopenta[1,2-b:4,3-b']dipyridin-5-one,5H-cyclopenta[2,1-b:4,3-c']dipyridin-5-one,5H-cyclopenta,,[1,2-b:3,4-c']dipyridin-5-one,5H-cyclopenta-[1,2-b:4,3-b']dipyridin-5-one,5H-cyclopenta[2,1-b:4,3-c']dipyridin-5-one,5H-cyclopenta-[2,1-b:3,4-c']dipyridin-5-one, and5H-cyclopenta-[2,1-b:3,4-b']dipyridin-5-one can be prepared according tothe method of Kloc, Michowski and Szulc, J. prakt. chemie, 319, 95q(1977). These ketones in accordance with Method I are derivatized intothe spiro-hydantoin products. Wolff-Kishner reduction or reductionaccording to Method VIII of the aforementioned ketones yields thecorresponding diazafluorene substrates such as5H-cyclopenta[2,1-b:4,3-b']dipyridine. These diazafluorene substratesare derivatized according to Methods II-IV to yield the correspondingspiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimidederivatives.

PREPARATION K

Synthetic substrates 8H-indeno[2,1-b]furan-8-one and8H-indeno[2,1-b]furan and their derivatives are prepared in accordancewith the following. Substituted and unsubstituted3-arylfuran-2-carboxylic acids are prepared according to a generalprocedure of Burgess, J. Org. Chem., 21, 102 (1956), wherein,4,5-dimethoxy-1-phenyl-2-butanone and related 2' to 4' substitutedphenyl analogs (e.g., 4,4-dimethoxy-1-(4'-fluorophenyl)-2-butanone,prepared according to the general procedure of Royals and Brannoch, J.Amer. Chem. Soc., 75, 2050 (1953)) are converted into3-phenylfuran-2-carboxylic acid methyl ester (e.g.,3'-(4'-fluorophenylfuran-2-carboxylic acid methyl ester) by the Darzensglycidic ester condensation (Darzens, Compt. Rend., 139, 1214 (1904)).This rearrangement of the glycidic ester yields the furoic ester. Thefuroic ester can be hydrolyzed in alkaline methanolic solution to yield,for example, 3-(4'-fluorophenyl)-furan-2-carboxylic acid. The furoicacid product can be cyclized via the aroyl chloride in the presence ofstannic chloride or aluminum chloride to yield the ketone, e.g.,6-fluoro-8H-indeno[2,1-b]furan-8-one. This ketone can be derivatized inaccordance with Method V. Hydantoin derivatization (Method I) yields thespirohydantoin, e.g.,spiro-(6-fluoro-8H-indeno[2,1-b]furan-8,4'-imidazolidine)-2',5'-dione.Reduction according to methods cited in Method VIII yields thecorresponding 8H-indeno[2,1-b]furan derivative which can be derivatizedin accordance with Methods II, III and IV into the correspondingspiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide.Furthermore, the spiro-derivatives may be further derivatized accordingto Method VI.

PREPARTION L

Synthetic substrates 4H-indeno[1,2-b]furan-4-one and4H-indeno[1,2-b]furan and their substituted analogs are prepared fromthe corresponding substituted and unsubstituted 2-arylfuran-3-carboxylicacids which are prepared according to a general procedure of Johnson, J.Chem. Soc., 1946, 895. The procedure involves the condensation of1,2-dichlorodiethyl ether with aroylacetic esters, such as ethylbenzoylacetate (Aldrich Chemical, Inc.), in the presence of 10% ammoniumhydroxide, yields a mixture of the 2-arylfuran-3-carboxylic ester and2-arylpyrrole-3-carboxylic ester (which can be used to prepare thecorresponding 4H-indeno[1,2-b]pyrrole-4-one) which are separated byfractionation. Saponification (10% KOH in 50% methanol) of the furanester, acidification and isolation yields the corresponding2-arylfuran-3-carboxylic acid. Treatment with phosphorus pentachloridefollowed by stannic chloride effects the Friedel-Crafts cyclization tothe ketone. Alternatively, thionyl chloride may be employed to preparethe acyl chloride followed by aluminum trichloride or stannic chlorideas the Friedel-Crafts catalyst in a solvent such as methylene chlorideto yield the process is summarized by this example: ##STR73##

Then according to Method I, the spiro-hydantoin derivative is prepared,e.g.,spiro-(6-chloro-4H-indeno[1,2-b]furan-4,4'-imidazolidine'2',5'-dione.

Analogous to earlier preparations, the ketone can be reduced accordingto Method VIII (Wolff-Kishner reduction) to yield the corresponding4H-indeno[1,2-b]furan. This heterocycle can derivatized according toMethod V. The derivatized or underivatized 4H-indeno[1,2-b]furanaccording to Method II, III and IV is derivatized to the correspondingspiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimiderespectively.

These spiro derivatives may be further derivatized in accordance withMethod VI.

PREPARATION M

Synthesis substrates 9H-pyrrolol[1,2-a]indole and9H-pyrrolol[1,2-a]indol-9-one and their derivatives are prepared inaccordance with the general methods of Josey and Jenner, J. Org. Chem.,27 (1962) 2466 and Mazzola et al., J. Org. Chem., 32 (1967) 486. Theprocess involves condensation of a substituted or unsubstituted methylanthranilate (Aldrich Chemical, Inc.) with 2,5-dimethoxytetrahydrofuran(Aldrich Chemical, Inc.) in glacial acetic acid. Ester hydrolysis of theresulting 1-(2-methoxycarbonylphenyl)pyrrole with 10-15% potassium orsodium hydroxide in aqueous alcohol (e.g., 50% methanol) yields afteracidification and subsequent work-up yields the corresponding1-(2-carboxyphenyl)pyrrole. This acid is then converted into thecorresponding acyl chloride to facilitate a Friedel-Crafts cyclizationto the ketone. The preferred method of preparing the acyl chloride iswith phosphorus pentachloride followed with stannic chloride as theFriedel-Crafts catalyst to cyclize the acyl chloride to the desiredketone. ##STR74## Wolf-Kishner reduction, see also Method VIII, via thesemicarbazones of the ketone yields the corresponding9H-pyrrolol[1,2-a]indole heterocycle.

The resulting ketone, such as 9H-pyrrolol[1,2-a]indole-9-one, isconverted into the corresponding spiro-hydantoin according to Method I,see Example XV. The resulting spiro-hydantoin can be further derivatizedin accordance with Method VI. Alternatively, the ketone may bederivatized according to Method V prior to spiro-hydantoinderivatization.

Similarly, 9H-pyrrolol[1,2-a]indole or its derivatives may bederivatized according to Method V. The derivatized or underivatizedheterocycle then may be further derivatized according to Methods II, IIIor IV to yield the corresponding spiro-thiazolidinedione,spiro-oxazolidinedione or spiro-succinimide respectively. Thesespiro-derivatives in turn may be derivatized in accordance with MethodVI.

PREPARATION N

Synthesis substrates 4H-indeno[2,3-c]-1,2,5-thiadiazol-4-one and4H-indeno[2,3-c]-1,25-thiadiazole and their derivatives are prepared inaccordance with the procedure of Mataka et al., Synthesis, 1979, 524 andMataka et al., J. Hetero. Chem., 17 (1980) 1681. The process involvesreacting tetranitrogentetrasulfide with 1,3-dihydro-2H-indeno-2-one(Aldrich Chemical, Inc.) in toluene at reflux yields: ##STR75##Alternatively, 5-fluoro-1,3-dihydro-2H-indeno-2-one (Flammang et al.,Eur. J. Med. Chem., 11 (1976) 83), 4-chloro-1,3-dihydro-2H-indeno-2-one(CA80:146166a) and 5-chloro-1,3-dihydro-2H-indeno-2-one (Olivier et al.,Bull. Soc. Chem. Fr., 11 (1973) 3096) can similarly be rated withtetranitrogentetrasulfide to yield the corresponding substitutedindenothiadiazole heterocycles. These heterocycles may be furtherderivatized in accordance with Method V and according to Methods II, IIIand IV derivatized into the corresponding spiro-thiazolidinedione,spiro-oxazolidinedione and spiro-succinimides respectively. These spiroderivatives in turn may be further derivatized according to Method VI.Oxidation of the 4H-indeno[2,3-c]-1,2,5-thiadiazole in accordance withMethod VII yields the ketone which may be derivatized in accordance withMethod I to yield the corresponding spiro-hydantoin, e.g.,spiro(4H-indeno[2,3-c']-1,2,5-thiadiazol-4,4'-imidazolidine)-2',5'-dione.This spiro hydantoin in turn may be derivatized further in accordancewith Method VI.

PREPARATION O

The triheterocyclic substrates thieno[2,3-b]pyrrolizine andthieno[2,3-b]pyrrolizin-4-one; thieno[3,2-b]pyrrolizine andthieno[3,2-b]pyrrolizin-4-one are prepared exactly according to Rault etal., Heterocycles, 20 (1983) 477. The process involves the cyclizationin boiling phosphoryl chloride of amide derivatives of2-(1-pyrrolyl)-3-thienylcarboxylic acid and3-(1-pyrrolyl)-2-thienylcarboxylic acid to yieldthieno[2,3-b]pyrrolizin-4-one and thieno[3,2-b]pyrrolizin-4-onerespectively. These ketones in accordance with Method I can bederivatized to the corresponding spiro-hydantoins:spiro-(thieno[3,2-b]pyrrolizin-4,4'-imidazolidine)-2',5'-dione andspiro-(thieno[3,2-b]pyrrolizin-4,4'-imidazolidine)-2',5'-dione. Boththieno[2,3-b]pyrrolizin-4-one and thieno[3,2-b]pyrrolizin-4-one can bereduced with 1.75 equivalents of lithium aluminum hydride in thepresence of 3.5 equivalents aluminum chloride to yield the corresponding4H-thieno-pyrrolizines quantitatively. The resultingthieno[2,3-b]pyrrolizine and thieno[3,2-b]pyrrolizine can be derivativedaccording to Methods II, III and IV into the correspondingspiro-thiazolidinediones, spiro-oxazolidinediones andspiro-succinimides, such asspiro-(thieno[3,2-b]pyrrolizin-4,5'-thiazolidine)-2',4'-dione,spiro-(thieno[2,3-b]pyrrolizin-4,5'-oxazolidine)-2',4'-dione andspiro-(thieno[3,2-b]pyrrolizin-4,3'-succinimide).

PREPARATION P

In an analogous manner to the preceding, the following startingmaterials may be derivatized in accordance with Methods I, II, III, IV,V, VII and VIII. Resulting spiro-derivative products may be furtherderivatized in agreement with Method VI.

a) 1- and 2-substituted -1H-indeno[1,2-c]pyrazol-4-ones ##STR76##wherein R¹ =H or lower alkyl and R² =lower alkyl or lower cycloakyl, areprepared according to Lemke and Sawney, J. Heterocyclic Chem. 19 (1982)1335 and Mosher and Soeder, J. Heterocyclic Chem., 8 (1971) 855.

b) 3-alkyl-4H-indeno[1,2-c]isoxazol-4-ones ##STR77## wherein R² =loweralkyl (preferably methy), are prepared according to Lemke et al., J.Heterocyclic Chem., 19 (1982) 363.

c) 3-alkyl-4H-indeno[1,2-c]isoxazol-4-ones ##STR78##

wherein R² =lower alkyl (preferably methyl), are prepared according toLemke and Martin, J. Heterocyclic Chem., 19 (1982) 1105.

d) 3-methyl-1H-pyrazolo[3',4':3,4]cyclopenta[1,2-b]pyridin-4-one and3-methyl-1H-pyrazolo[3',4':3,4]cyclopenta[2,1-c]pyridin-4-one ##STR79##respectively are prepared according to Mosher and Banks, J. HeterocyclicChem., 8 (1972) 1005.

e) The following indenopyrimidinone ##STR80## is prepared according toCA90:38958q.

f) 5H-indeno[1,2-c]pyridazine and 3-methyl-5H-indeno[1,2-c]pyridazine##STR81## is prepared according to Loriga et al., Farmaco, Ed. Sci., 34(1979) 72.

After spiro-derivatization the corresponding spiro-hydantoin,spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimideproducts are obtained.

PREPARATION Q

Synthesis substrates, 4H-indeno[2,3-c]-1,2,5-oxadiazol-4-one and4H-ideno-[2,3-c]-1,2,5-oxadiazole and their derivatives are prepared inaccordance with the following process (see Korte and Storiko, ChemischeBerichte, 94 (1961) 1956). The starting material4-oximino-3-phenyl-isoxazole is prepared according to Ber. dtsch. Chem.Ges., 24 (1891) 140, see also Hantzsch and Heilbron, Chemische Berichte,43 (1910) 68: ##STR82## and hydrolyzed with water and treated withsodium carbonate to effect a rearrangement according to Korte, ibid.##STR83##

The resulting acid is cyclized by stepwise treatment with phosphoruspentachloride in methylene chloride followed by Friedel-Craftscyclization catalyzed by stannic chloride. The resulting ketone isderivatized in accordance with Method I to yield the spiro-hydantoin##STR84## which may be further derivatized according to Method VI. Theketone may be reduced according to Method VIII (Wolff-Kishner reduction)and further derivatized in accordance with Method V. The substitutedheterocycle may be oxidized back to the ketone in accordance to MethodVII and then derivatized to the spiro-hydantoin. Alternately theheterocycle may be derivatized in accordance with Methods II, III and IVto the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione andspiro-succinimide. These may be further derivatized in accordance withMethod VI.

EXAMPLE I 9-Hydroxy-9H-fluorene-9-carboxylic acid methyl ester (1)##STR85## 9-Hydroxy-9H-fluorene-9-carboxylic acid (Aldrich Chemical,Inc.) (20.0 g, 88.4 mmol) was added to 100 mL methanol saturated withhydrogen chloride and mixture was stirred at reflux for 4 h. Thecrystalline material obtained on cooling was collected by filtration andwashed with cold 1:1 ethyl acetate/hexane to provide after drying (1),15.8 g (74%). Spiro-(9H-fluorene-9,5'-oxazolidine)-2',4'-dione (2)##STR86## To a stirred solution of sodium (190 mg, 8.26 mmol) in 20 mLabsolute ethanol was added urea (500 mg, 8.26 mmol) and9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester (1) (2.00 g, 8.26mmol). The mixture was stirred at reflux under nitrogen for 15 h. Aftercooling to room temperature, the reaction mixture was poured into 100 mLwater and acidified with 2N aqueous hydrochloric acid to precipitate theproduct which was collected by filtration, washed with water, and driedto provide 1.5 g crude (2). Recrystallization from ethyl acetate gave260 mg (12%): m.p. 225°-257° C. A second crop, 620 mg (30%), wasobtained by evaporation of the mother liquor followed byrecrystallization from ethyl acetate/hexane. M/e⁺. 251. For thepreparation of oxazolidinediones from α-hydroxy esters using urea andsodium ethoxide, see: Stoughton, J. Am. Chem. Soc. (1941) 63, 2376.EXAMPLE II 2-Fluoro-9H-fluorene-9-carboxylic acid (3) ##STR87## Undernitrogen atmosphere, n-butyllithium (1.25 eq, 0.170 mL, 65 mL of a 2.6Mhexane solution) was added dropwise over 30 min. to a stirred 0.5° C.solution of 2-fluorofluorene (prepared according to U.S. ApplicationSer. Nos. 368,630 and 368,631) (25.0 g, 0.136 mmol) in 500 mL dry THF.After an additional 35 min. a flow of dry carbon dioxide gas into thesolution was commenced and continued for 15 min. at 0°-15° C. and 45min. at room temperature. 2N aqueous hydrochloric acid (200 mL) wasadded, and the mixture was transferred to a separatory funnel. Theaqueous layer was separated and extracted 1×100 mL ethyl acetate. Thecombined organic phases were washed 1×100 mL brine, dried (MgSO₄), andevaporated to leave a dark residue which was triturated with 250 mLhexane to leave 16.6 g crude acid. Recrystallation from acetonitrilegave 10.2 g of the acid (3). A second crop of 2.0 g was obtained fromthe concentrated filtrate. Chromatography of the filtrate and theconcentrated hexane extract on silica gel using 10-50% ethylacetate/hexane provided another 2.8 g. Total yield: 15.0 g (48%).2-Fluoro-9H-fluorene-9-carboxylic acid methyl ester (4) ##STR88## Acetylchloride (33 mL) was added dropwise to a stirred, ice-cold solution of2-fluoro-9H-fluorene-9-carboxylic acid (3) (16.7 g, 73.2 mmol) in 200 mLmethanol and the solution was then refluxed for 4 h. Solvent removalleft the crude product which was recrystallized from methanol to provide(4), 14.1 g (79%): m.p. 90°-92° C. (from hexane). For the preparation of9H-fluorene-9-carboxylic acid from fluorene using phenyllithium andesterification using methanolic hydrogen chloride see: Bavin, Anal.Chem. (1960) 32, 554. 2-Fluoro-9-hydroxy-9H-fluorene-9-carboxylic acidmethyl ester (5) ##STR89##

To a stirred solution of sodium (1.25 eq, 22.3 mmol, 510 mg) in 100 mLmethanol was added 2-fluoro-9H-fluorene-9-carboxylic acid methyl ester(4) (4.33 g, 17.9 mmol). After 15 min. a flow of dry oxygen into thesolution was commenced and continued for 1 h. Some of a solution ofsodium bisulfite (24.5 g) in 300 mL water was added until the reactionbecame cloudy. The mixture was then poured into the remaining bisulfitesolution. After cooling in ice, the solid that separated was collectedby filtration, washed well with water, and dried to provide (5), 4.05 g(88%).

Spiro-(2-fluoro-9H-fluorene-9,5'-oxazolidine)-2',4'-dione (6) ##STR90##To a stirred solution of sodium (1.03 eq, 130 mg) in 13 mL absoluteethanol was added 2-fluoro-9-hydroxy-9H-fluorene-9-carboxylic acidmethyl ester (5) (1.42 g, 5.5 mmol) and urea (5.5 mmol, 330 mg). Themixture was then refluxed 15 h. After cooling to room temperature, themixture was poured into 65 mL water and acidified with 2N aqueoushydrochloric acid. The yellow solid that separated was collected, washedwith water, and dried to give 1.19 g crude material. Chromatography onsilica gel using 1-100% methanol/chloroform gave pure (6), 580 mg (39%).m/e⁺. 269. EXAMPLE III 9-Chloro-9H-fluorene-9-carboxylic acid methylester (7) ##STR91## A mixture of 9-hydroxy-9H-fluorene-9-carboxylic acidmethyl ester (1) (5.00 g, 20.8 mmol) and 50 mL thionyl chloride washeated at reflux for 3 h. The thionyl chloride was removed on therotavapor to leave a solid residue which was redissolved in 50 mLbenzene and then evaporated to remove traces of thionyl chloride. Theresulting material was recrystallized from acetic acid to give (7), 3.23g (60%): m.p. 111°-114° C. An additional 960 mg (18%) of product wasobtained by chromatography of the reduced filtrate on silica gel using10% ethyl acetate/hexane.Spiro-[9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (8) ##STR92##

A mixture of 9-chloro-9H-fluorene-9-carboxylic acid methyl ester (7)(4.21 g, 16.3 mmol) and thiourea (1.24 g, 16.3 mmol) in 150 mL dioxanewas heated at reflux for 10 h. After cooling to room temperature, thefine white solid present was collected by filtration and washed withdioxane providing (8), 1.31 g (30%). The gummy residue which remained inthe flask was chromatographed on silica gel using 10-20%methanol/chloroform to give another 220 mg (5%) of (7): m.p. 320°-322°C. (dec). For the preparation of 2-imino-4-thiazolidinones from α-haloacid halides using thiourea in dioxane, see: Skinner, J. Org. Chem.(1961) 26, 1450.

Spiro-(9H-fluorene-9,5'-thiazolidine)-2',4'-dione (9) ##STR93## Amixture of spiro-[9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (8) (1.19g, 4.47 mmol), 24 mL methanol, and 24 mL concentrated hydrochloric acidwas refluxed 4 h. The reaction mixture was cooled in ice and the whiteprecipitate was collected by filtration, washed with water, and dried toprovide 640 mg crude (9). Recrystallization from acetonitrile gave 490mg (41%): m.p. 253°-255° C. A second crop of 80 mg (7%) was obtainedfrom the mother liquor. Calc. % C 67.40, % H 3.39; % N 5.24: meas. % C67.46, % H 3.34, N 5.32. For the hydrolysis of 2-amino-4-thiazolones tothiazolidinediones using methanolic hydrogen chloride, see: Koltai,Tetrahedron (1973) 29, 2781. EXAMPLE IV9-Chloro-2-fluoro-9H-fluorene-9-carboxylic acid methyl ester (10)##STR94## A mixture of 2-fluoro-9-hydroxy-9H-fluorene-9-carboxylic acidmethyl ester (5) (4.00 g, 15.5 mmol) and 50 mL thionyl chloride wasrefluxed 3 h. After the thionyl chloride was removed on the rotavapor,the material was redissolved in 50 mL benzene and the benzene thenevaporated to remove trace thionyl chloride. The crude product, 4.3 g(100%), was used without further purification.Spiro-[2-fluoro-9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (11)##STR95## A mixture of 9-chloro-2-fluoro-9H-fluorene-9-carboxylic acidmethyl ester (10) (4.31 g, 15.6 mmol) and thiourea (1.1 eq, 17.2 mmol,1.31 g) in 140 mL dioxane was refluxed for 10 h. After cooling to roomtemperature, the fine white precipitate was collected by filtration andwashed with water providing (11), 1.28 g (29%). An additional 1.3 g(29%) of (11) was obtained by chromatography of the reduced filtrate onsilica gel using 5-50% methanol/chloroform.Spiro-(2-fluoro-9H-fluorene-9,5'-thiazolidine)-2',4'-dione (12)##STR96## A mixture ofspiro-[2-fluoro-9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (11) (1.85 g,6.51 mmol), 35 mL methanol, and 35 mL concentrated hydrochloric acid washeated at reflux for 6 h. After cooling to room temperature, the whiteprecipitate was collected by filtration and washed with water to provide1.22 g of crude (12). Recrystallization from ethanol provided threecrops totaling 870 mg (47%): m.p. 272°-276° C. (dec). m/e⁺. 285. EXAMPLEV 2,7-Difluoro-9H-fluorene-9-carboxylic acid (13) ##STR97##

To a stirred, room temperature solution of 2,7-difluorofluorene(prepared according to U.S. application Ser. Nos. 368,630 and 368,631)(10.0 g, 49.5 mmol in 75 mL dry diethyl ether under a nitrogenatmosphere was added over 15 min n-butyllithium (1.25 eq, 61.9 mmol, 24mL of a 2.6M hexane solution). The solution was refluxed 30 min., cooledto room temperature, and then quickly poured onto an ether slurry of alarge excess of powdered dry ice. After the dry ice evaporated, themixture was transferred to a separatory funnel along with 100 mL 2Naqueous hydrochloric acid and 50 mL ethyl acetate. After shaking well,the organic layer was separated and evaporated to dryness. The residuewas extracted 2×100 mL warm (50° C.) 2% aqueous sodium hydroxide andthen the extract was acidified with concentrated hydrochloric acid toprecipitate the impure acid which was collected by filtration and washedwith water. This material was dissolved in 50% ethyl acetate/hexane andpassed through a 50 mm×7 silica gel column using the same solvent toremove highly colored, baseline impurities and to provide (13)sufficiently pure to be used in the next step, 7.91 g (65%): m.p.128°-130° C. (from benzene).

2,7-Difluoro-9H-fluorene-9-carboxylic acid methyl ester (14) ##STR98##Acetyl chloride (13 mL) was added dropwise to a stirred, ice-coldsolution of 2,7-difluoro-9H-fluorene-9-carboxylic acid (14) (6.90 g, 28mmol) in 77 mL methanol. The mixture was then heated at reflux for 4 h.The product which crystallized upon cooling in ice was collected byfiltration and washed with cold methanol to provide (14), 5.15 g (71%):m.p. 161°-163° C. (from toluene).2,7-Difluoro-9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester (15)##STR99## 2,7-Difluoro-9H-fluorene-9-carboxylic acid methyl ester (14)(4.73 g, 18.2 mmol) was added to a solution of sodium (1.25 eq, 22.7mmol, 520 mg) in 100 mL methanol. After 15 min., a flow of dry oxygeninto the solution as commenced and continued for 1 h. Some of a solutionof 24.5 g sodium bisulfite in 800 mL water was added until the mixtureturned cloudy and then the whole was poured into the remaining bisulfitesolution. The solid was collected by filtration, washed with water, anddried to provide (15), 4.68 g (93%): m.p. 174°-176° C. (from benzene).9-Chloro-2,7-difluoro-9H-fluorene-9-carboxylic acid methyl ester (16)##STR100## A mixture of 2,7-difluoro-9-hydroxy-9H-fluorene-9-carboxylicacid methyl ester (15) (3.63 g, 13.1 mmol) and 50 mL thionyl chloridewas heated at reflux for 4 h. The reaction mixture was then diluted with300 mL benzene and evaporated to leave (16), 3.7 g (96%), which was usedin the next step without further purification: m.p. 140°-142° C. (fromacetonitrile).Spiro-[2,7-difluoro-9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (17)##STR101## A mixture of 9-chloro-2,7-difluoro-9H-fluorene-9-carboxylicacid methyl ester (16) (3.56 g, 12.1 mmol) and thiourea (1.1 eq, 13.3mmol, 1.01 g) in 110 mL dry dioxane was heated at reflux for 12 h. Aftercooling to room temperature and in ice, the white precipitate wascollected by filtration, washed with dioxane, and dried to provide (17),490 mg (13%). The concentrated filtrate and the gummy residue whichremained in the flask were individually chromatographed on silica gelusing 5-20% methanol/chloroform to provide another 1.00 g (27%) product:m.p. >300° C.Spiro-(2,7-difluoro-9H-fluorene-9,5'-thiazolidine)-2',4'-dione (18)##STR102## A mixture ofspiro-[2,7-difluoro-9H-fluorene-(2'-amino-4'-thiazolone)] (17) (1.17 g,3.87 mmol), 21 mL methanol, and 21 mL concentrated hydrochloric acid wasrefluxed for 6 h. The reaction mixture was cooled in ice and theoff-white precipitate was collected by filtration, washed with water,and dried to provide 900 mg crude (18). This material waschromatographed on silica gel using 5-10% methanol/chloroform to yieldpure (18), 530 mg (45%): m.p. 260°-263° C. (dec). Calc. % C 59.40, % H2.33, % N 4.62: meas. % C 59.47, % H 2.42, % N 4.64. EXAMPLE VISpiro-(9H-fluoren-9,3'-succinimide) (20) ##STR103##9H-fluoren-9-carboxylic acid methyl ester (19), which was prepared byrefluxing 9H-fluoren-9-carboxylic acid (Aldrich Chemical, Inc.) inHCl/MeOH, (10.0 g, 44.6 mmol) was added to a solution of sodium (1.2 eq,53.5 mmol, 1.23 g) in 100 mL methanol. After 15 min., 2-chloroacetamide(1.1 eq, 49.1 mmol, 4.59 g) was added and the mixture was allowed tostir at room temperature under nitrogen for two (2) days. The reactionmixture was poured into 400 mL of cold 2.5% w/v aqueous sodium hydroxideand the insoluble material was removed by filtration. The filtrate waschilled and acidified with concentrated hydrochloric acid to precipitatethe spiro-succinimide which was collected and air dried to provide 6.7 g(60%). Recrystallization from methanol gave purified (20), 4.28 g (39%).m.p. 237°-239° C. Calc. % C 77.09, % H 4.45, % N 5.62: meas. % C 77.17,% H 4.55, % N 5.58. EXAMPLE VIISpiro-(2-fluoro-9H-fluoren-9,3'-succinimide) (21) ##STR104## Thespiro-succinimide (21), m.p. 248°-250° C., was prepared analogous toExample VI except from (4) in 25% yield. Calc. % C 71.90, % H 3.77, % N5.24: meas. % C 71.97, % H 3.87, % N 5.33 EXAMPLE VIII5H-Indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (22) ##STR105##Under a nitrogen atmosphere, n-butyllithium (1.2 eq, 105 mmol, 65 mL ofa 2.6M hexane solution) was added dropwise over a 30 min. period to astirred 0°-5° C. solution of 4-azafluorene (14.65 g, 87.6 mmol) in 150mL dry tetrahydrofuran (dried and distilled from LAH). After 1 h 20 min.the reaction mixture was poured into an ether slurry containing a largeexcess of dry ice. Solvents were allowed to evaporate overnight. Theresidue was suspended in 300 mL methanol, chilled and 60 mL acetylchloride was added dropwise over 45 min. and the mixture stirred for 22h at room temperature. Purification by chromatography (30% ethylacetate/hexane on silica gel) and solvent evaporation yields 16.3 g(83%) of (22). 5-Hydroxy-5H-indeno[1,2-b]pyridine-5-carboxylic acidmethyl ester (23) ##STR106##

To a stirred solution of sodium (1.1 eq, 60.1 mmol, 1.38 g) in 150 mLdry methanol was added a solution of5-hydroxy-5H-indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (22)(12.3 g, 54.6 mmol) in 50 mL dry methanol. The solution was cooled inice and, after 15 min., a flow of dry oxygen was begun and continued for1 h. Then the reaction mixture was poured into a solution of 12 g sodiumbisulfite in 200 mL water. After 30 min. the mixture was evaporated todryness. The resulting solid was triturated with 2×100 mL acetone andfiltered. The remaining inorganic salts were removed by filtration. Thefiltrate was evaporated to yield 24.2 g wet pink solid of (23). Dryingin vacuo over phosphorus pentaoxide yielded 12.5 g crude (23).Recrystallization from ethyl acetate yielded two crops 8.06 g (61%) and2.54 g (19%) of (23).

5-Chloro-5H-Indeno[1,2-b]Pyridine-5-Carboxylic Acid Methyl Ester (24)##STR107## A mixture of 5-hydroxy-5H-indeno[1,2-b]pyridine-5-carboxylicacid methyl ester (23) (8.06 g, 33.4 mmol) in 200 mL thionyl chloridewas heated at reflux for 4 h. The thionyl chloride was removed on therotavapor to leave a residue which was partitioned between water andchloroform and neutralized with saturated sodium bicarbonate. Afterfurther extractions with chloroform the combined chloroform extractswere dried over magnesium sulfate and evaporated to yield 7.87 g (91%)of (24).Spiro-[5H-indeno[1,2-b]pyridine-5,5'-(2'-amino-4'-thiazolone)](25)##STR108## A mixture of 5-chloro-5H-indeno[1,2-b]pyridine-5-carboxylicacid methyl ester (24) (7.87 g, 30.4 mmol), thiourea (1.2 eq, 36.4 mmol,2.77 g) and sodium acetate (1.1 eq, 33.4 mmol, 2.74 g) in 140 mL glacialacetic acid was refluxed for 40 min. Then 100 mL water was added and thepH was adjusted to 6.7 with hydrochloric acid. The aqueous portion wasdecanted from the precipitate, followed by additional 50 mL water wash.The dried residue was treated with ethyl acetate and the resultingcrystalline solid was collected by filtration and dried to yield 1.81 g(32%) of (25).Spiro-(5H-Indeno[1,2-b]Pyridine-5,5'-Thiazolidine)-2',4'-Dione (26)##STR109## A mixture ofspiro-[5H-indeno[1,2-b]pyridine-5,5'-(2'-amino-4'-thiazolone)](25) (1.00g, 3.74 mmol) was stirred at reflux in a solution of 100 mL methanol andconcentrated hydrochloric acid (1:1) for 2 h. The mixture was thenconcentrated to approximately 10 mL with heat and reduced pressure,chilled on ice and neutralized with sodium hydroxide solution. Theresulting precipitate was collected by filtration and washed with water.Purification of the dried precipitate by chromatography (silica gelusing 2.5-7% methanol/chloroform) yielded a product after solventevaporation, 400 mg. Recrystallization of the residue from ethanolyielded crystalline (26). m/e⁺. 268. IR strong bands at 1700 and 1745cm⁻¹. EXAMPLE IX Spiro-(5H-indeno[1,2-b]pyridine-5,3'-succinimide) (27)##STR110## The ester (22) (4.00 g, 17.8 mmol) was added all at once to astirred, room temperature solution of sodium methoxide in methanol(sodium metal, 1.2 eq, 21.3 mmol, 490 mg and 40 mL dry methanol). After15 min., chloroacetamide (1.1 eq, 19.5 mmol, 1.83 g) was added and themixture was left to stir at room temperature under nitrogen. After twodays the reaction mixture was poured into 100 mL 1N sodium hydroxide,cooled in ice and the pH was adjusted with concentrated hydrochloricacid to pH 7. The precipitated solid was collected by filtration andwashed with cold water. The dried solid (2.02 g) was recrystallized fromethyl acetate with charcoal treatment to yield 1.03 g (23%) crystalline(27). m.p. 245°-246° C. Calc. % C 71.99, % H 4.03, % N 11.20: meas. % C71.85, % H 4.14, % N 11.17. EXAMPLE X 5H-Indeno[1,2-b]pyridin-5-one (28)##STR111## See general oxidation method of Sprinxak, J. Am. Chem. Soc.,80 (1958) 5449. 4-Azafluorene (5.0 g, 30 mmol) was dissolved in 50 mLanhydrous pyridine containing in solution 2 mL Triton B solution(prepared by evaporating 5 mL of 40% Triton B in methanol (AldrichChemical, Inc.) and 5 mL pyridine with heat and reduced pressurefollowed by q.s. to 10 mL with pyridine). Then air was continuouslybubbled through the solution with stirring. An addition of 2 mL Triton Bsolution was made twice more at two-hour intervals. After six hours thereaction mixture was evaporated to dryness. The residue was trituratedin 30 mL water and extracted four times with ethyl acetate (total volume200 mL). The combined ethyl acetate extracts were dried over anhydroussodium sulfate. After filtration and evaporation, the residue waschromatographed (silica gel and chloroform) to yield after evaporationof the solvent 4.5 g (83%) of (28). m.p. 132°-136° C. (reported 142°C.). Spiro-(5H-Indeno[1,2-b]Pyridine-5,4'-Imidazolidine)-2',5'-Dione(29) ##STR112## 5H-Indeno[1,2-b]pyridine-5-one (4.0 g, 22 mmol) wasmixed with potassium cyanide (1.6 g, 24 mmol) and ammonium carbonate(5.3 g, 55 mmol) in 90% ethanol (75 mL) in a pressure reactor and heatedat 105° C. for 40 hr. The mixture was poured into 300 mL of water,acidified with conc. HCl (pH 1), and filtered. The filtrate wasneutralized and the solid which formed collected by filtration, washedwith water, and dried to yield 4.5 g. This solid was crystallized fromethyl acetate to yield 3.2 g of product. (This material was no longersoluble in ethyl acetate after the first crystallization). m/e⁺. 251.EXAMPLE XISpiro-(7-nitro-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione (30)##STR113## Spiro-(indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione(29) (1.0 g, 4 mmol) was added to cold concentrated sulfuric acid (10mL) and stirred in an ice bath as concentrated nitric acid was addeddropwise over about 10 min. The mixture was allowed to warm to roomtemperature and stirred overnight; the resulting solution was pouredonto ice and the solution neutralized with concentrated aqueous sodiumhydroxide. The solid which formed was collected by filtration, washedwith a small volume of water, and dried. The product was dissolved inwarm water (30 mL) by the addition of sodium hydroxide solution treatedwith Norite decoloring charcoal, filtered through a celite bed and thebed washed with a small volume of warm dilute base. The combinedfiltrate and wash were neutralized with hydrochloric acid to yield asolid which was collected by filtration, washed with water and dried toyield 0.76 g of (30). Calc. % C 56.76, % H 2.72, % N 18.91: meas. % C56.59, % H 2.83, % N 18.87. m/e⁺. 296. EXAMPLE XIISpiro-(7-bromo-indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione(31) ##STR114##Spiro-(indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione (29) (1.0 g,4 mmol) was dissolved in cold 70% sulfuric acid (50 mL). The solutionwas heated to 50° C., and N-bromosuccinimide (0.78 g, 4.3 mmol) wasadded in small portions with stirring. After stirring at 50° C. for 2 h,the reaction was poured onto ice, and the solution was neutralized withconcentrated aqueous sodium hydroxide. The solid which formed wascollected by filtration and washed with water. The sample was dissolvedin 30 mL of warm water by addition of aqueous sodium hydroxide thentreated with Norite, filtered through a celite bed and washed with warmdilute base, and the combined filtrate and wash were acidified withhydrochloric acid (to pH 6). The solid was collected by filtration,washed with water, and dried to yield 0.88 g of (31). m/e⁺. 329. EXAMPLEXIII 4H-indeno[1,2-b]thiophen-4-one (35) ##STR115## To methylanthranilate (90.0 g, 77 mL, 595 mmol, 1.0 eq) was added hydrochloricacid (120 mL of conc., 1450 mmol, 2.4 eq diluted with 100 mL distilledwater). The resulting mixture of solid and liquid was heated to refluxwith stirring while protected from light. The hot clear solution wascooled to 5° C. whereupon a solid precipitated. To this stirred mixturewas added sodium nitrite solution (41.09 g, 596 mmol, 1.0 eq in 90 mLdistilled water) at a rate to maintain the reaction temperature below 5°C. After 1.5 h fluoroboric acid (95 g, 48% in water) was added rapidlyand the resulting suspension was stirred for an additional 30 min. at-10° to 0° C. The suspended solid was collected by filtration, washedwith 100 mL cold water, 120 mL cold methanol and 500 mL ether. Theresulting pink solid was dried in vacuo over concentrated sulfuric acidto yield 39.5 g of (32) as a pink solid (m.p. 93°-98° C. withdecomposition, reported 102° C. with decomposition Org. Reactions 5,219).

To a diazo salt (32) (39.5 g, 158 mmol, 1.0 eq) in thiophene (75 mL)stirred suspension was dropwise added during 1 h a solution consistingof 3,5-dimethylpyrazole (15.80 g, 164 mmol, 1.04 eq) and hydroquinone(1.91 g, 17 mmol, 0.11 eq) in 125 mL thiophene at 0° C. After 2.5 hadditional stirring at 0°-5° C. the reaction was stirred overnight atambient temperature (see J. Org. Chem., 46 (1981) 3960). Evaporationwith heat and reduced pressure yielded a brown semisolid. Columnchromatography (silica gel, 1:9 to 1:4 ethyl ether/petroleum ether)yields 19.4 g. Distillation (bp 141°-160° C., 4 mmHg) yields 15.1 g of(33).

To 15.1 g of (33) was added methanolic potassium hydroxide (12.8 g KOHin 200 mL methanol) and the reaction mixture was refluxed for 4 hwhereupon potassium hydroxide (2.5 g) was added. After 5 h totalrefluxing, the starting material (33) was completely hydrolyzed (silicagel, 40% Pet ether/ether). To the cooled mixture was added 250 mL waterand the diluted mixture was extracted with 250 mL ethyl ether. The etherextract was back extracted with 150 mL 10% KOH. The combined aqueousfractions were cooled and acidified with concentrated hydrochloric acidto pH 2. The acidified slurry was then extracted with diethyl ether(3×200 mL), the ether extracts washed with brine (150 mL) then driedwith anhydrous magnesium sulfate. After filtration and evaporation, 23.7g tan solid resulted. m.p. 80° C. (reported m.p. 93°-94° C., J. Med.Chem., 9 (1966) 551). To the acid (13.7 g, 69.2 mmol, 1.0 eq) was addedthionyl chloride (25.3 mL, 213 mmol, 3.1 eq) and the mixture wasrefluxed for 2 h. After cooling the reaction mixture was evaporated withreduced pressure and heat with 3×100 mL benzene additions to result in15 g of (34) as a dark oil.

Under nitrogen, a stannic chloride solution (SnCl₄, 9.1 g, 4.1 mL, 1.25eq in 40 mL benzene) was added over 20 min. to a benzene (100 mL)solution of the acid chloride (34) (15 g, 69.2 mmol) at 0°-4° C. withmechanical stirring. After a total of 30 min. the reaction mixture waspoured into 200 cc ice containing 100 mL 1N hydrochloric acid. (See J.Org. Chem., 35 (1970) 872). Ethyl acetate extractions (600 mL) of theaqueous mixture yielded a dark organic extract. Washing the organicextract with 100 mL 100% sodium hydroxide, 100 mL water (2X) yielded anorange ethyl acetate extract which was dried over anhydrons magnesiumsulfate. Filtration and evaporation yielded a dark residue. Columnchromatography (silica gel, 1:9 ethyl ether/petroleum ether) yields apurified 4.5 g sample of orange (35). m.p. 99.5°-101.5° C. from hexane.(lit. 101° C., J. Org. Chem. 35 (1970) 872). Calc. % C 70.94, % H 3.25,% S 17.22: meas. % C 70.98, % H 3.33, % S 17.16.

Spiro-(4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione (36)##STR116## To a glass-lined, High-pressure steel reaction vessel wasadded ketone (35) (373 mg, 2 mmol), potassium cyanide (406 mg, 5 mmol),ammonium carbonate (577 mg, 6 mmol) and ethanol (15 mL). The sealedvessel was heated at 110° C. for 24 h. The dark reaction mixture waspoured into water and acidified with concentrated hydrochloric acid topH 1. The resulting dark solid was collected by filtration andresolubilized in 10% sodium hydroxide (30 mL), treated with charcoal andfiltered. The filtrate was acidified with concentrated hydrochloricacid. The resulting precipitate was collected by filtration and dried.The solid was dissolved in dimethylformamide, treated with Darco G-60and filtered through a Celite pad. Dilution with water (3× volume)resulted in a precipitate which was collected by filtration. Thecollected solid was dissolved in 10% sodium hydroxide (3 mL), filtered,and the filtrate was acidified with conc. hydrochloric acid, the whiteprecipitate collected by filtration, washed with water and dried at 105°C. to yield 110 mg of (36). m.p. 336°-8° C. Calc. % C 60.92, % H 3.15, %N 10.96: meas. % C 60.83, % H 3.22, % N 10.97. EXAMPLE XIV8H-Indeno[2,1-b]thiophen-8-one (38): ##STR117## Thionyl chloride (60.3g, 37 mL, 500 mmol, 3.6 eq) was added at 25° C. to o-bromobenzoic acid(Aldrich Chemical, Inc.) (28.1 g, 140 mmol, 1.0 eq). After addition thereaction mixture was heated to 80° C. for 13 h. Evaporation with heatand reduced pressure partially reduced the volume. Then under nitrogenatmosphere 100 mL methylene chloride followed by 3-bromothiophene(Aldrich Chemical, Inc.) (22.8 g, 13.1 mL, 140 mmol, 1.0 eq) in 100 mLmethylene chloride were added to acyl chloride intermediate. Thenaluminum trichloride (23.9 g, 179 mmol, 1.3 eq) was added in smallportions to the reaction mixture at 0° C. After addition, the reactionmixture was allowed to slowly reach room temperature. After 17 h thereaction was quenched by the slow addition of 150 mL 2N hydrochloricacid. Water (2×150 mL) and brine (100 mL) washing, drying over anhydrousmagnesium sulfate, filtration and evaporation of the filtrate in vacuoyielded approximately 50 g of an oil of (37) which solidified in thefreezer. IR 1645 cm⁻¹ for diaryl ketone.

Diaryl ketone (37) (44 g, 480 mmol, 4 eq) and activated copper (preparedfrom aqueous copper sulfate, zinc dust, 5% hydrochloric acid) (30 g, 480mmol, 4 eq) in 200 mL dimethylformamide were refluxed for 6.5 h. Afterthe cooling the reaction mixture was filtered and 150 mL water added.The filtrate was extracted with ethyl ether (5×150 mL). The combinedether extracts were washed with 150 mL 1N hydrochloric acid, 150 mLwater and 150 mL brine. Then the ether solution was dried over anhydrousmagnesium sulfate, filtered and evaporated to yield a solid, 18.6 g(79%). Recrystallization from hexane yielded purified (38) m.p.111°-112° C. Calc. % C 70.97, % H 3.25, % S 17.22: meas. % C 70.71, % H3.26, % S 17.12.

Spiro-(8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione (39)##STR118## To a glass-lined, high-pressure steel reaction vessel wasadded ketone (38) (931.2 mg, 5 mmol), potassium cyanide (1.01 g, 12.5mmol), ammonium carbonate (1.45 g, 18 mmol) and 25 mL ethanol. Thesealed vessel was heated at 115°-120° C. for 20 h. The work-up procedurewas very similar to that for spiro-hydantoin (36) of Example XIII. Thepurified product (39), 200 mg, gave m/e⁺. 256. Calc. % C 60.92, % H3.15, % N 10.96: meas. % C 60.88, % H 3.22, % H 10.79. EXAMPLE IVSpiro-(9H-pyrrolol[1,2-a]indol-9,4'-imidazolidine)-2',4'-dione (41)##STR119## 9H-Pyrrolol[1,2-a]indole-9-one (40) was prepared exactlyaccording to Josey and Jenner, J. Org. Chem., 27 (1962) 2466. The ketone(40) (2.5 g, 15 mmol), potassium cyanide (2.44 g, 37.5 mmol), ammoniumcarbonate (4.85 g, 45 mmol) and 50 mL 90% ethanol were added with mixingto a 125 cc stainless steel pressure reaction vessel. The sealed vesselwas heated to 115°-118° C. for 48 h. The work-up was as in Example XIIIin the work-up of (36). The collected and dried sample, 650 mg of (41),gave decomposition at >290° C. Calc. % C 65.26, % H 3.79, % N 17.56:meas. % C 65.16, % H 4.00, % N 17.59. EXAMPLE XVISpiro-(9H-indeno[2,1-c]pyridin-9,4'-imidazolidine]-2',5'-dione (43)##STR120## 2-Azafluoren-9-one (42) was prepared from3-mesitoyl-4-phenyl-pyridine exactly according to Fuson and Miller, J.Am. Chem. Soc., 79 (1957) 3477. m.p. 152°-153° C. (reported155.5°-156.5° C. by Fuson and Miller, ibid). The ketone (42) (0.5 g, 2.8mmol), potassium cyanide (0.2 g, 3.1% mmol), ammonium carbonate (1.0 g,11 mmol) and 10 mL absolute ethanol were added with mixing to a 40 ccstainless steel pressure reactor. The sealed vessel was heated at115°-120° C. for 30 h. The cooled reaction mixture was poured into 75 mLwater, acidified with concentrated hydrochloric acid, filtered, thefiltrate was made basic with 10% sodium hydroxide and filtered. Thefiltrate was neutralized with hydrochloric acid, the precipitatecollected, washed with cold water and dried to yield 0.11 g of (43).m/e⁺. 251. EXAMPLE XVIISpiro-(2-chloro-7-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione (45)##STR121## The spiro-hydantoin (44),spiro-(2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione, was preparedexactly according to U.S. application Ser. Nos. 368,630 and 368,631. Amixture of (44) (5.36 g, 20 mmol), ferric chloride (0.25 g), glacialacetic acid solution of chlorine gas (5 g Cl₂ in 25 mL HOAc) and 200 mLglacial acetic acid were heated at 75° C. overnight. The cooled reactionmixture was poured into 200 mL water, stirred and the solid wascollected by filtration. After water washes, the solid product was driedwith 50° C. heat in vacuo to yield 2.3 g of (45). Calc. % C 59.52, % H2.66, % N 9.25: meas. % C 59.35, % H 2.77, % N 9.26. EXAMPLE XVIII7-fluoro-5H-indeno[1,2-b]pyridine (50)

The procedure used for the preparation of 5-fluoro-1-indanone is that ofOlivier and Marechal (E. Bull. Soc. Chim. Fr. (1973) 3092-3095) withmodifications. The conversion of the ketone to7-fluoro-5H-indeno[1,2-b]pyridine followed the general proceduredescribed by Parcell and Hauck (J. Org. Chem. (1963) 28, 3468-3473) forthe preparation of 5H-indeno[1,2-b]pyridine from 1-indanone. ##STR122##Aluminum chloride (350 g, 2.62 mol) was covered with 650 mL methylenechloride and, while stirring under nitrogen, a solution of3-chloropropionyl chloride (400 g, 3.15 mol, 300 mL) in 250 mL methylenechloride was added over 80 min. After 15 min., a solution offluorobenzene (256 g, 2.66 mol, 250 mL) in 250 mL methylene chloride wasadded over 1 h 35 min. The reaction mixture was stirred, under nitrogen,at room temperature overnight (ca 18 h). The mixture was then pouredonto 2.5 kg ice and transferred to a 4 L separatory funnel. Aftershaking well, the organic layer was removed and the aqueous portion wasextracted with 2×50 mL methylene chloride. The combined organic extractswere washed with 3×200 mL saturated aqueous sodium bicarbonate and 1×200mL brine, dried (MgSO₄), and evaporated to leave an oil whichcrystallized on cooling. Recrystallization from 2 L hexane gave 325 g(67%). The filtrate was concentrated to 500 mL and cooled to provideanother 42 g (9%) of product (46). ##STR123##3-Chloro-1-(4-fluorophenyl)propanone (46) (366 g, 1.97 mol) and 2.2 Lconcentrated sulfuric acid were combined in a 5 L flask equipped with amechanical stirrer and heated over a period of 80 min. to 120° C. andthen maintained at that temperature for 30 min. Hydrogen chlorideevolution began at about 80° C. The reaction mixture was then cooled to20° C., poured onto 5 kg of ice in a 22 L flask equipped with a bottomdrain and a mechanical stirrer, and extracted with 6×1 L chloroform. Thecombined extracts were washed with 2×1 L saturated aqueous sodiumbicarbonate and 1×1 L brine, dried (MgSO₄), and concentrated to leave adark oil. Distillation gave the ketone, (47) 97.9 g (33%), bp 61°-66°C./0.15-0.2 mm, discolored by some dark material which was carried overduring the process. ##STR124## A solution of 5-fluoro-1-indanone (47)(20.2 g, 0.135 mol), p-toluene-sulfonic acid monohydrate (0.015 eq, 390mg), and piperidine (1.1 eq, 0.148 mol, 15 mL) in 300 mL toluene wasrefluxed under a Dean-Stark trap for 30 h. The reaction mixture wasconcentrated and distilled to provide the enamine, (48) 8.6 g (29%); bp95°-100° C./1.5 mm. ##STR125## A solution of the enamine (8.6 g, 40mmol) in 10 mL dry DMF was added all at once to a stirred solution ofbromopropylamine hydrobromide (1.0 eq, 8.67 g) in 15 mL DMF. The stirredmixture was heated to 100° C. under nitrogen and then kept at thattemperature for 4 h. The reaction mixture was poured into 60 mL cold 2Naqueous hydrochloric acid and extracted with 2×50 mL ethyl ether toremove any non-basic material. The aqueous solution was then coveredwith 50 mL ether, chilled, and basified using concentrated sodiumhydroxide. After separating the organic layer, the aqueous portion wasextracted with 2×50 mL ether and the combined extracts were washed with1×50 mL brine, dried (MgSO₄), and concentrated to leave 7.8 g of a darkoil. Distillation provided the tetrahydropyridine, 3.46 g (46%); bp83°-86° C./0.15 mm. ##STR126## A mixture of the tetrahydropyridine (49)(3.19 g, 16.9 mmol), 10 mL xylene, 10 mL nitrobenzene, and 350 mg 10%palladium on carbon was refluxed for 4 h under a Dean-Stark trap undernitrogen. The reaction mixture was then cooled to room temperature andfiltered through Celite, washing with ethyl acetate. The filtrate wasextracted with 3×20 mL 2N aqueous hydrochloric acid and then thecombined extracts were washed with 2×25 mL ethyl ether to removenon-basic material. Basification using solid potassium carbonateresulted in the precipitation of a dark green solid that was collectedby filtration and washed well with water. This material 2.3 g (75%), wasjudged sufficiently pure by NMR to use in the next step. The materialcan further be purified by chromatography on silica gel using 30% ethylacetate/hexane to give a yellow solid of (50) mp 80°-84° C.

The product (50) can be oxidized in accordance with Method VII andderivatized according to Method I into the correspondingspiro-hydantoin.

The product (50) can be derivatized in accordance with Methods II, IIIand IV into the corresponding spiro-thiazolidinedione,spiro-oxazolidinedione and spiro-succinimide.

EXAMPLE XIX

Following the foregoing text of preparations and examples, from readilyavailable starting materials, the following spiro-derivatives of thepresent invention are prepared by analogy. All structional permutationsoccasioned by the substitution patterns and the values of U and Z on thefollowing tricyclic structures are fully comtemplated and intended asevidenced by the table entries.

UNSUBSTITUTED PARENT STRUCTURES FOR COMPOUNDS 1-328: A-D

    ______________________________________                                         ##STR127##                                                                    ##STR128##                                                                    ##STR129##                                                                    ##STR130##                                                                   Compound Ring                                                                 No.      Substitution      U                                                  ______________________________________                                        1-4:A-D  7-F               NH, NCH.sub.3, S, O                                5-8:A-D  6-F               NH, NCH.sub.3, S, O                                9-12:A-D 5-F               NH, NCH.sub.3, S, O                                13-16:A-D                                                                              4-F               NH, NCH.sub.3, S, O                                17-20:A-D                                                                              7-F, 2-CH.sub.3   NH, NCH.sub.3 , S, O                               21-24:A-D                                                                              7-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                25-28:A-D                                                                              6-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                29-32:A-D                                                                              6-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                33-36:A-D                                                                              5-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                37-40:A-D                                                                              5-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                41-44:A-D                                                                              4-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                45-48:A-D                                                                              4-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                49-52:A-D                                                                              7-Cl              NH, NCH.sub.3, S, O                                53-56:A-D                                                                              6-Cl              NH, NCH.sub.3, S, O                                57-60:A-D                                                                              5-Cl              NH, NCH.sub.3, S, O                                61-64:A-D                                                                              4-Cl              NH, NCH.sub.3, S, O                                65-68:A-D                                                                              7-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                69-72:A-D                                                                              7-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                73-76:A-D                                                                              6-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                77-80:A-D                                                                              6-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                81-84:A-D                                                                              5-Cl, 2-CH.sub.3  NH, NCH.sub.3 , S, O                               85-88:A-D                                                                              5-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                89-92:A-D                                                                              4-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                93-96:A-D                                                                              4-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                97-100:A-D                                                                             7-F, 6-F          NH, NCH.sub.3, S, O                                101-104:A-D                                                                            7-F, 5-F          NH, NCH.sub.3, S, O                                105-108:A-D                                                                            7-F, 4-F          NH, NCH.sub.3, S, O                                107-112:A-D                                                                            6-F, 5-F          NH, NCH.sub.3, S, O                                113-116:A-D                                                                            6-F, 4-F          NH, NCH.sub.3, S, O                                117-120:A-D                                                                            5-F, 4-F          NH, NCH.sub.3, S, O                                121-124:A-D                                                                            7-Cl, 6-Cl        NH, NCH.sub.3, S, O                                125-128:A-D                                                                            7-Cl, 5-Cl        NH, NCH.sub.3, S, O                                129-132:A-D                                                                            7-Cl, 4-Cl        NH, NCH.sub.3, S, O                                133-136:A-D                                                                            6-Cl, 5-Cl        NH, NCH.sub.3, S, O                                137-140:A-D                                                                            6-Cl, 4-Cl        NH, NCH.sub.3, S, O                                141-144:A-D                                                                            5-Cl, 4-Cl        NH, NCH.sub.3, S, O                                145-148:A-D                                                                            7-F, 6-Cl         NH, NCH.sub.3, S, O                                149-152:A- D                                                                           7-F, 5-Cl         NH, NCH.sub.3, S, O                                153-156:A-D                                                                            7-F, 4-Cl         NH, NCH.sub.3, S, O                                157-160:A-D                                                                            6-F, 7-Cl         NH, NCH.sub.3, S, O                                161-164:A-D                                                                            6-F, 5-Cl         NH, NCH.sub.3, S, O                                165-168:A-D                                                                            6-F, 4-Cl         NH, NCH.sub.3, S, O                                169-172:A-D                                                                            5-F, 7-Cl         NH, NCH.sub.3, S, O                                173-176:A-D                                                                            5-F, 6-Cl         NH, NCH.sub.3, S, O                                177-180:A-D                                                                            5-F, 4-Cl         NH, NCH.sub.3, S, O                                181-184:A-D                                                                            4-F, 7-Cl         NH, NCH.sub.3, S, O                                185-188:A-D                                                                            4-F, 6-Cl         NH, NCH.sub.3, S, O                                189-192:A-D                                                                            4-F, 5-Cl         NH, NCH.sub.3, S, O                                193-196:A-D                                                                            7-F, 6-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                197-200:A-D                                                                            7-F, 5-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                201-204:A-D                                                                            7-F, 4-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                205-208:A-D                                                                            7-F, 6-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                209-212:A-D                                                                            7-F, 5-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                213-216:A-D                                                                            7-F, 4-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                217-220:A-D                                                                            6-F, 5-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                221-224:A-D                                                                            6-F, 4-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                225-228:A-D                                                                            6-F, 5-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                229-232:A-D                                                                            6-F, 4-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                233-236:A-D                                                                            5-F, 4-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                237-240:A-D                                                                            5-F, 4-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                241-244:A-D                                                                            6-Cl, 5-Cl, 2-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                245-248:A-D                                                                            6-Cl, 5-Cl, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                249-252:A-D                                                                            6-Cl, 4-Cl, 2-CH.sub.3                                                                          NH, NCH.sub.2, S, O                                253-256:A-D                                                                            6-Cl, 4-Cl, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                257-260:A-D                                                                            6-(CH.sub.3S)     NH, NCH.sub.3, S, O                                261-264:A-D                                                                            6-(CH.sub.3S), 2-CH.sub.3                                                                       NH, NCH.sub.3, S, O                                265-268:A-D                                                                            6-(CH.sub.3S), 3-CH.sub.3                                                                       NH, NCH.sub.3, S, O                                269-272:A-D                                                                            6-(CH.sub.3S(O))  NH, NCH.sub.3, S, O                                273-276:A-D                                                                            6-(CH.sub.3S(O)), 2-CH.sub.3                                                                    NH, NCH.sub.3, S, O                                277-280:A-D                                                                            6-(CH.sub.3S(O)), 3-CH.sub.3                                                                    NH, NCH.sub.3, S, O                                281-284:A-D                                                                            7-F, 6-(CH.sub.3S)                                                                              NH, NCH.sub.3, S, O                                285-288:A-D                                                                            5-F, 6-(CH.sub.3S)                                                                              NH, NCH.sub.3, S, O                                289-292:A-D                                                                            4-F, 6-(CH.sub.3S)                                                                              NH, NCH.sub.3, S, O                                293-296:A-D                                                                            6-CF.sub.3        NH, NCH.sub.3, S, O                                297-300:A-D                                                                            6-CF.sub.3, 2-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                301-304:A-D                                                                            6-CF.sub.3, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                305-308:A-D                                                                            6-[CH(CH.sub.3)COOH]                                                                            NH, NCH.sub.3, S, O                                309-312:A-D                                                                            6-[CH(CH.sub.3)COOH],                                                                           NH, NCH.sub.3, S, O                                         2-CH.sub.3                                                           313-316:A-D                                                                            6-[CH(CH.sub.3)COOH],                                                                           NH, NCH.sub.3, S, O                                         3-CH.sub.3                                                           317-320:A-D                                                                            6-CH.sub.3        NH, NCH.sub.3, S, O                                321-324:A-D                                                                            6-CH.sub. 3, 2-CH.sub.3                                                                         NH, NCH.sub.3, S, O                                325-328:A-D                                                                            6-CH.sub.3, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURES FOR COMPOUNDS 329-656: A-D

    ______________________________________                                         ##STR131##                                                                    ##STR132##                                                                   Compound Ring                                                                 No.      Substitution      U                                                  ______________________________________                                        329-332:A-D                                                                            7-F               NH, NCH.sub.3, S, O                                333-336:A-D                                                                            6-F               NH, NCH.sub.3, S, O                                337-340:A-D                                                                            5-F               NH, NCH.sub.3, S, O                                341-344:A-D                                                                            8-F               NH, NCH.sub.3, S, O                                345-348:A-D                                                                            7-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                349-352:A-D                                                                            7-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                353-356:A-D                                                                            6-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                357-360:A-D                                                                            6-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                361-364:A-D                                                                            5-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                365-368:A-D                                                                            5-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                369-372:A-D                                                                            8-F, 2-CH.sub.3   NH, NCH.sub.3, S, O                                373-376:A-D                                                                            8-F, 3-CH.sub.3   NH, NCH.sub.3, S, O                                377-380:A-D                                                                            7-Cl              NH, NCH.sub.3, S, O                                381-384:A-D                                                                            6-Cl              NH, NCH.sub.3, S, O                                385-388:A-D                                                                            5-Cl              NH, NCH.sub.3, S, O                                389-392:A-D                                                                            8-Cl              NH, NCH.sub.3, S, O                                393-396:A-D                                                                            7-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                397:400:A-D                                                                            7-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                401-404:A-D                                                                            6-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                405-408:A-D                                                                            6-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                409-412:A-D                                                                            5-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                413-416:A-D                                                                            5-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                417-420:A-D                                                                            8-Cl, 2-CH.sub.3  NH, NCH.sub.3, S, O                                421-424:A-D                                                                            8-Cl, 3-CH.sub.3  NH, NCH.sub.3, S, O                                425-428:A-D                                                                            7-F, 6-F          NH, NCH.sub.3, S, O                                429-432:A-D                                                                            7-F, 5-F          NH, NCH.sub.3, S, O                                433-436:A-D                                                                            7-F, 8-F          NH, NCH.sub.3, S, O                                437-440:A-D                                                                            6-F, 5-F          NH, NCH.sub.3, S, O                                441-444:A-D                                                                            6-F, 8-F          NH, NCH.sub.3, S, O                                445-448:A-D                                                                            5-F, 8-F          NH, NCH.sub.3, S, O                                449-452:A-D                                                                            7-Cl, 6-Cl        NH, NCH.sub.3, S, O                                453-456:A-D                                                                            7-Cl, 5-Cl        NH, NCH.sub.3, S, O                                457-460:A-D                                                                            7-Cl, 8-Cl        NH, NCH.sub.3, S, O                                461-464:A-D                                                                            6-Cl, 5-Cl        NH, NCH.sub.3, S, O                                465-468:A-D                                                                            6-Cl, 8-Cl        NH, NCH.sub.3, S, O                                469-472:A-D                                                                            5-Cl, 8-Cl        NH, NCH.sub.3, S, O                                473-476:A-D                                                                            7-F, 6-Cl         NH, NCH.sub.3, S, O                                477-480:A-D                                                                            7-F, 5-Cl         NH, NCH.sub.3, S, O                                481-484:A-D                                                                            7-F, 8-Cl         NH, NCH.sub.3, S, O                                485-488:A-D                                                                            6-F, 7-Cl         NH, NCH.sub.3, S, O                                489-492:A-D                                                                            6-F, 5-Cl         NH, NCH.sub.3, S, O                                493-496:A-D                                                                            6-F, 8-Cl         NH, NCH.sub.3, S, O                                497-500:A-D                                                                            5-F, 7-Cl         NH, NCH.sub.3, S, O                                501-504:A-D                                                                            5-F, 6-Cl         NH, NCH.sub.3, S, O                                505-508:A-D                                                                            5-F, 8-Cl         NH, NCH.sub.3, S, O                                509-512:A-D                                                                            8-F, 7-Cl         NH, NCH.sub.3, S, O                                513-516:A-D                                                                            8-F, 6-Cl         NH, NCH.sub.3, S, O                                517-520:A-D                                                                            8-F, 5-Cl         NH, NCH.sub.3, S, O                                521-524:A-D                                                                            7-F, 6-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                525-528:A-D                                                                            7-F, 5-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                529-532:A-D                                                                            7-F, 8-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                533-536:A-D                                                                            7-F, 6-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                537-540:A-D                                                                            7-F, 5-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                541-544:A-D                                                                            7-F, 8-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                545-548:A-D                                                                            6-F, 5-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                549-552:A-D                                                                            6-F, 8-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                553-556:A-D                                                                            6-F, 5-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                557-560:A-D                                                                            6-F, 8-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                561-564:A-D                                                                            5-F, 8-F, 2-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                565-568:A-D                                                                            5-F, 8-F, 3-CH.sub.3                                                                            NH, NCH.sub.3, S, O                                569-572:A-D                                                                            6-Cl, 5-Cl, 2-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                573-576:A-D                                                                            6-Cl, 5-Cl, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                577-580:A-D                                                                            6-Cl, 8-Cl, 2-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                581-584:A-D                                                                            6-Cl, 8-Cl, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                585-588:A-D                                                                            6-(CH.sub.3S)     NH, NCH.sub.3, S, O                                589-592:A-D                                                                            6-(CH.sub.3S), 2-CH.sub.3                                                                       NH, NCH.sub.3, S, O                                593-596:A-D                                                                            6-(CH.sub.3S), 3-CH.sub.3                                                                       NH, NCH.sub.3, S, O                                597-600:A-D                                                                            6-(CH.sub.3S(O))  NH, NCH.sub.3, S, O                                601-604:A-D                                                                            6-(CH.sub.3S(O)), 2-CH.sub.3                                                                    NH, NCH.sub.3, S, O                                605-608:A-D                                                                            6-(CH.sub.3S(O)), 3-CH.sub.3                                                                    NH, NCH.sub.3, S, O                                609-612:A-D                                                                            7-F, 6-(CH.sub.3S)                                                                              NH, NCH.sub.3, S, O                                613-616:A-D                                                                            5-F, 6-(CH.sub.3S)                                                                              NH, NCH.sub.3, S, O                                617-620:A-D                                                                            8-F, 6-(CH.sub.3S)                                                                              NH, NCH.sub.3, S, O                                621-624:A-D                                                                            6-CF.sub.3        NH, NCH.sub.3, S, O                                625-628:A-D                                                                            6-CF.sub.3, 2-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                629-632:A-D                                                                            6-CF.sub.3, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                633-636:A-D                                                                            6-[CH(CH.sub.3)COOH]                                                                            NH, NCH.sub.3, S, O                                637-640:A-D                                                                            6-[CH(CH.sub.3)COOH],                                                                           NH, NCH.sub.3, S, O                                         2-CH.sub.3                                                           641-644:A-D                                                                            6-[CH(CH.sub.3)COOH],                                                                           NH, NCH.sub.3, S, O                                         3-CH.sub.3                                                           645-648:A-D                                                                            6-CH.sub.3        NH, NCH.sub.3, S, O                                649-652:A-D                                                                            6-CH.sub.3, 2-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                653-656:A-D                                                                            6-CH.sub.3, 3-CH.sub.3                                                                          NH, NCH.sub.3, S, O                                ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURES FOR COMPOUNDS 657-706: A-D

    ______________________________________                                         ##STR133##                                                                    ##STR134##                                                                    ##STR135##                                                                    ##STR136##                                                                                  Ring                                                           Compound No.   Substitution                                                   ______________________________________                                        657:A-D        6-F                                                            658:A-D        7-F                                                            659:A-D        8-F                                                            660:A-D        9-F                                                            661:A-D        3-F                                                            662:A-D        6-F, 3-F                                                       663:A-D        7-F, 3-F                                                       664:A-D        8-F, 3-F                                                       665:A-D        9-F, 3-F                                                       666:A-D        6-Cl                                                           667:A-D        7-Cl                                                           668:A-D        8-Cl                                                           669:A-D        9-Cl                                                           670:A-D        6-Cl, 3-F                                                      671:A-D        7-Cl, 3-F                                                      672:A-D        8-Cl, 3-F                                                      673:A-D        9-Cl, 3-F                                                      674:A-D        6-F, 7-F                                                       675:A-D        6-F, 8-F                                                       676:A-D        6-F, 9-F                                                       677:A-D        7-F, 8-F                                                       678:A-D        7-F, 9-F                                                       679:A-D        8-F, 9-F                                                       680:A-D        3-F, 7-F, 8-F                                                  681:A-D        7-(CH.sub.3S)                                                  682:A-D        7-(CH.sub.3S(O))                                               683:A-D        7-[CH(CH.sub.3)COOH]                                           684:A-D        7-[CH(CH.sub.3)COOH], 3-CH.sub.3                               685:A-D        7-[CH(CH.sub.3)COOH], 2-CH.sub. 3                              686:A-D        7-[CH(CH.sub.2)COOH], 4-CH.sub.3                               687:A-D        6-[CH(CH.sub.3)COOH]                                           687:A-D        6-[CH(CH.sub.3)COOH], 3-CH.sub.3                               688:A-D        6-[CH(CH.sub.3)COOH], 2-CH.sub.3                               689:A-D        6-[CH(CH.sub.3)COOH], 4-CH.sub.3                               690:A-D        7-CH.sub.3                                                     691:A-D        7-(CH.sub.3O)                                                  692:A-D        7-CF.sub.3                                                     693:A-D        7-COOH                                                         694:A-D        7-CONH.sub.2                                                   695:A-D        6-CH.sub.3 COOH                                                696:A-D        6-CH.sub.2 COOH, 3-CH.sub.3                                    697:A-D        6-CH.sub.2 COOH, 2-CH.sub.3                                    698:A-D        6-CH.sub.2 COOH, 4-CH.sub.3                                    699:A-D        6-COOH                                                         700:A-D        6-CH.sub.3NH.sub.2                                             701:A-D        7-CH.sub.2 COOH                                                702:A-D        7-CH.sub.2 COOH, 3-CH.sub.3                                    703:A-D        7-CH.sub.2 COOH, 2-CH.sub.3                                    704:A-D        7-CH.sub.2 COOH, 4-CH.sub.3                                    705:A-D        7-COOH, 3-CH.sub.3                                             706:A-D        7-CH.sub.2NH.sub.2                                             ______________________________________                                    

    ______________________________________                                         ##STR137##                                                                    ##STR138##                                                                    ##STR139##                                                                    ##STR140##                                                                                   Ring                                                          Compound No.    Substitution                                                  ______________________________________                                        707:A-D         8-F                                                           708:A-D         7-F                                                           709:A-D         6-F                                                           710:A-D         5-F                                                           711:A-D         7-Cl                                                          712:A-D         5-F, 6-F                                                      713:A-D         5-F, 7-F                                                      714:A-D         5-F, 8-F                                                      715:A-D         6-F, 7-F                                                      716:A-D         6-F, 8-F                                                      717:A-D         7-F, 8-F                                                      718:A-D         7-(CH.sub.3S)                                                 719:A-D         7-(CH.sub.3S(O))                                              720:A-D         7-COOH                                                        721:A-D         7-CH.sub.3                                                    722:A-D         7-CF.sub.3                                                    723:A-D         7-[CH(CH.sub.2)COOH]                                          724:A-D         7-[CH(CH.sub.2)COOH], 2-CH.sub.3                              725:A-D         7-[CH(CH.sub.2)COOH], 3-CH.sub.3                              726:A-D         7-[CH(CH.sub.2)COOH], 4-CH.sub.3                              727:A-D         6-[CH(CH.sub.2)COOH], 2-CH.sub.3                              728:A-D         6-[CH(CH.sub.2)COOH], 3-CH.sub.3                              729:A-D         6-[CH(CH.sub.2)COOH], 4-CH.sub.3                              730:A-D         6-[CH(CH.sub.2)COOH], 5-CH.sub.3                              ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURES FOR PARENT COMPOUNDS 731-766:A-D

    ______________________________________                                         ##STR141##                                                                    ##STR142##                                                                    ##STR143##                                                                    ##STR144##                                                                                   Ring                                                          Compound No.    Substitution                                                  ______________________________________                                        731:A-D         8-F                                                           732:A-D         7-F                                                           733:A-D         6-F                                                           734:A-D         5-F                                                           735:A-D         7-Cl                                                          736:A-D         5-F, 6-F                                                      737:A-D         5-F, 7-F                                                      738:A-D         5-F, 8-F                                                      739:A-D         6-F, 7-F                                                      740:A-D         6-F, 8-F                                                      741:A-D         7-F, 8-F                                                      742:A-D         7-(CH.sub.2S)                                                 743:A-D         7-(CH.sub.2 S(O))                                             744:A-D         7-COOH                                                        745:A-D         7-CH.sub.3                                                    746:A-D         7-CF.sub.3                                                    747:A-D         7-[CH(CH.sub.3)COOH]                                          748:A-D         7-[CH(CH.sub.3)COOH], 1-CH.sub.3                              749:A-D         7-[CH(CH.sub.3)COOH], 3-CH.sub.3                              750:A-D         7-[CH(CH.sub.3)COOH], 4-CH.sub.3                              751:A-D         6-[CH(CH.sub.2)COOH]                                          752:A-D         6-[CH(CH.sub.2)COOH], 1-CH.sub.3                              753:A-D         6-[CH(CH.sub.2)COOH], 3-CH.sub.3                              754:A-D         6-[CH(CH.sub.2)COOH], 4-CH.sub.3                              755:A-D         7-CONH.sub.2                                                  756:A-D         6-CONH.sub.2                                                  757:A-D         7-CH.sub.2 COOH                                               758:A-D         7-CH.sub.2 COOH, 1-CH.sub.3                                   759:A-D         7-CH.sub.2 COOH, 3-CH.sub.3                                   760:A-D         7-CH.sub.2 COOH, 4-CH.sub.3                                   761:A-D         6-CH.sub.2 COOH                                               762:A-D         6-CH.sub.2 COOH, 1-CH.sub.3                                   763:A-D         6-CH.sub.2 COOH, 3-CH.sub.3                                   764:A-D         6-CH.sub.2 COOH, 4-CH.sub.3                                   765:A-D         6-COOH                                                        766:A-D         6-Cl                                                          ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURES FOR COMPOUNDS 767-792:A-D

    ______________________________________                                         ##STR145##                                                                    ##STR146##                                                                    ##STR147##                                                                    ##STR148##                                                                                      Ring                                                       Compound No.       Substitution                                               ______________________________________                                        767:A-D            9-F                                                        768:A-D            8-F                                                        769:A-D            7-F                                                        770:A-D            6-F                                                        771:A-D            7-Cl                                                       772:A-D            8-Cl                                                       773:A-D            7-(CH.sub.2S)                                              774:A-D            7-(CH.sub.3S(O))                                           775:A-D            7-[CH(CH.sub.3)COOH]                                       776:A-D            6-[CH(CH.sub.3)COOH]                                       777:A-D            7-COOH                                                     778:A-D            7-CONH.sub.2                                               779:A-D            7-CF.sub.3                                                 780:A-D            7-CH.sub.3 COOH                                            781:A-D            8-CH.sub.3 COOH                                            782:A-D            7-CH.sub.3 COOC.sub.2 H.sub.5                              783:A-D            8-CH.sub.3 COOC.sub.2 H.sub.5                              784:A-D            7-F, 8-F                                                   785:A-D            7-Cl, 8-Cl                                                 786:A-D            7-CH.sub.3                                                 787:A-D            7-CH.sub.2NH.sub.3                                         788:A-D            7-NO.sub.3                                                 789:A-D            8-NO.sub.3                                                 790:A-D            7-CH.sub.3OH                                               791:A-D            8-COOH                                                     792:A-D            8-CONH.sub.2                                               ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURES FOR COMPOUNDS 793-847:A-D

    ______________________________________                                         ##STR149##                                                                    ##STR150##                                                                    ##STR151##                                                                    ##STR152##                                                                                   Ring                                                          Compound No.    Substitution                                                  ______________________________________                                        793:A-D         8-F                                                           794:A-D         7-F                                                           795:A-D         6-F                                                           796:A-D         5-F                                                           797:A-D         8-F, 1-CH.sub.3                                               798:A-D         8-F, 2-CH.sub.3                                               799:A-D         8-F, 3-CH.sub.3                                               800:A-D         7-F, 1-CH.sub.3                                               801:A-D         7-F, 2-CH.sub.3                                               802:A-D         7-F, 3-CH.sub.3                                               803:A-D         6-F, 1-CH.sub.3                                               804:A-D         6-F, 2-CH.sub.3                                               805:A-D         6-F, 3-CH.sub.3                                               806:A-D         5-F, 1-CH.sub.3                                               807:A-D         5-F, 2-CH.sub.3                                               808:A-D         5-F, 3-CH.sub.3                                               809:A-D         7-Cl                                                          810:A-D         7-Cl, 1-CH.sub.3                                              811:A-D         7-Cl, 2-CH.sub.3                                              812:A-D         7-Cl, 3-CH.sub.3                                              813:A-D         7-(CH.sub.2S)                                                 814:A-D         7-(CH.sub.2S), 1-CH.sub.3                                     815:A-D         7-(CH.sub.2S), 2-CH.sub.3                                     816:A-D         7-(CH.sub.2S), 3-CH.sub.3                                     817:A-D         7-[CH.sub. 3S(O)]                                             818:A-D         7-[CH.sub.3S(O)], 1-CH.sub.3                                  819:A-D         7-[CH.sub.3S(O)], 2-CH.sub.3                                  820:A-D         7-[CH.sub.3S(O)], 3-CH.sub.3                                  821:A-D         6-F, 7-F                                                      822:A-D         7-Cl, 6-F                                                     823:A-D         7-[CH(CH.sub.3)COOH]                                          824:A-D         7-[CH(CH.sub.2)COOH], 1-CH.sub.3                              825:A-D         7-[CH(CH.sub.2)COOH], 2-CH.sub.3                              826:A-D         7-[CH(CH.sub.2)COOH], 3-CH.sub.3                              827:A-D         6-[CH(CH.sub.2)COOH],                                         828:A-D         6-[CH(CH.sub.2)COOH], 1-CH.sub.3                              829:A-D         6-[CH(CH.sub.2)COOH], 2-CH.sub.3                              830:A-D         6-[CH(CH.sub.2)COOH], 3-CH.sub.3                              831:A-D         6-CH.sub.2 COOH                                               832:A-D         6-CH.sub.2 COOH, 1-CH.sub.3                                   833:A-D         6-CH.sub.2 COOH, 2-CH.sub.3                                   834:A-D         6-CH.sub.2 COOH, 3-CH.sub.3                                   835:A-D         7-CH.sub.3 COOH                                               836:A-D         7-CH.sub.3 COOH, 1-CH.sub.3                                   837:A-D         7-CH.sub.3 COOH, 2-CH.sub.3                                   838:A-D         7-CH.sub.3 COOH, 3-CH.sub.3                                   839:A-D         6-Cl                                                          840:A-D         6-COOH                                                        841:A-D         6-CONH.sub.2                                                  842:A-D         7-COOH                                                        843:A-D         7-CONH.sub.3                                                  844:A-D         6-OCH.sub.3                                                   845:A-D         3-Cl                                                          846:A-D         6-CH.sub.2 NH.sub.3                                           847:A-D         7-CH.sub.2 NH.sub.3                                           ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURE FOR COMPOUNDS 848-876:A-D

    ______________________________________                                         ##STR153##                                                                    ##STR154##                                                                    ##STR155##                                                                    ##STR156##                                                                                  Ring                                                           Compound No.   Substitution  Z                                                ______________________________________                                        848-849:A-D    6-F           O, S                                             850-851:A-D    7-F           O, S                                             852-853:A-D    6-Cl          O, S                                             854-855:A-D    7-Cl          O, S                                             856-857:A-D    6-COOH        O, S                                             858-859:A-D    6-(CH.sub.3S) O, S                                             860-861:A-D    6-[CH(CH.sub.3)COOH]                                                                        O, S                                             862-863:A-D    7-[CH(CH.sub.3)COOH]                                                                        O, S                                             864-865:A-D    6-CH.sub.3 COOH                                                                             O, S                                             866-867:A-D    7-CH.sub.3 COOH                                                                             O, S                                             868-869:A-D    7-COOH        O, S                                             870-871:A-D    6-CONH.sub.3  O, S                                             872-873:A-D    7-CONH.sub.3  O, S                                             874-875:A-D    6-F, 7-F      O, S                                             ______________________________________                                    

UNSUBSTITUTED PARENT STRUCTURE FOR COMPOUNDS 877-940:A-D

    ______________________________________                                         ##STR157##                                                                    ##STR158##                                                                    ##STR159##                                                                    ##STR160##                                                                                Ring                                                             Compound No. Substitution                                                     ______________________________________                                        877:A-D      1-F                                                              878:A-D      2-F                                                              879:A-D      3-F                                                              880:A-D      4-F                                                              881:A-D      1-F, 5-F                                                         882:A-D      1-F, 6-F                                                         883:A-D      1-F, 7-F                                                         884:A-D      1-F, 8-F                                                         885:A-D      2-F, 5-F                                                         886:A-D      2-F, 6-F                                                         887:A-D      2-F, 7-F                                                         888:A-D      3-F, 5-F                                                         889:A-D      3-F, 6-F                                                         890:A-D      4-F, 5-F                                                         891:A-D      2-Cl                                                             892:A-D      2-Cl, 5-F                                                        893:A-D      2-Cl, 6-F                                                        894:A-D      2-Cl, 7-F                                                        895:A-D      2-Cl, 8-F                                                        896:A-D      2-F, 3-F, 7-F                                                    897:A-D      2-F, 7-CH.sub.3                                                  898:A-D      2-F, 7-(CH.sub.3S)                                               899:A-D      2-F, 7-(CH.sub.3S(O))                                            900:A-D      2-F, 7-(CH.sub.3SO.sub.2)                                        901:A-D      2-Cl, 7-(CH.sub.3S)                                              902:A-D      2-Cl, 7-(CH.sub.3S(O))                                           903:A-D      2-Cl, 7-(CH.sub.3SO.sub.3)                                       904:A-D      2-F, 7-(CH.sub.3 O)                                              905:A-D      7-F, 2-COOH                                                      906:A-D      6-F, 2-COOH                                                      907:A-D      7-F, 3-COOH                                                      908:A-D      6-F, 3-COOH                                                      909:A-D      2-F, 2-[CH(CH.sub.3)COOH]                                        910:A-D      2-Cl, 2-[CH(CH.sub.3)COOH]                                       911:A-D      2-F, 2-[CH(CH.sub.3)COOH]                                        912:A-D      2-Cl, 2-[CH(CH.sub.3)COOH]                                       913:A-D      2-(CH.sub.3S), 7-[CH(CH.sub.3)COOH]                              914:A-D      2-[CH.sub.3S(O)], 7-[CH(CH.sub.3)COOH]                           915:A-D      2-(CH.sub.3S), 6-[CH(CH.sub.3)COOH]                              916:A-D      2-[CH.sub.3S(O)], 6-[CH(CH.sub.3)COOH]                           917:A-D      7-F, 2-CONH.sub.2                                                918:A-D      7-Cl, 2-CONH.sub.2                                               919:A-D      2-F, 3-F, 7-(CH.sub.3S)                                          920:A-D      2-F, 3-F, 7-[CH.sub.3 S(O)]                                      921:A-D      2-F, 7-CF.sub.3                                                  922:A-D      2-F, 7-OH                                                        923:A-D      2-F, 6-OH                                                        924:A-D      2-F, 5-OH                                                        925:A-D      2-F, 7-(CH.sub.3O)                                               926:A-D      2-COOH, 6-F, 7-F                                                 927:A-D      3-COOH, 6-F, 7-F                                                 928:A-D      2-(CH.sub.3S), 3-F                                               929:A-D      2-(CH.sub.2S), 4-F                                               930:A-D      2-F, 3-F, 7-(CH.sub.2S)                                          931:A-D      2-F, 3-F, 7-[CH.sub.2S(O)]                                       932:A-D      2-F, 3-(CH.sub.2S), 7-F                                          933:A-D      2-F, 3-[CH.sub.2 S(O)], 7-F                                      934:A-D      1-F, 7-NO.sub.2                                                  935:A-D      2-F, 7-NO.sub.2                                                  936:A-D      3-F, 7-NO.sub.2                                                  937:A-D      4-F, 7-NO.sub.2                                                  938:A-D      2-[CH.sub.2 (CH.sub.3)COOH]                                      939:A-D      2-CH.sub.2 COOH                                                  940:A-D      2-CH.sub.3 COOH, 7-F                                             ______________________________________                                    

EXAMPLE XX ##STR161## Preferred derivatives from Example XIX may beoxidized in accordance with Method VI to yield the correspondingN-oxides. Similarly, other N-oxides are prepared from otherspiro-tricyclic aromatic azine derivatives of the present invention.

Alternatively, an indeopyridine or indenopyridine ketone may be oxidizedin accordance with Method V to the corresponding N-oxide prior to spiroderivatization according to Methods I, III or IV. ##STR162##

EXAMPLE XXI

The sodium salt ofspiro-(2-fluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione,spiro-(6-fluoro-9H-pyrrolol[1,2-a]indol-9,4'-imidazolidine)-2,4'-dione,spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dioneor any of their related spiro tricyclic congeners which are the subjectof the present invention are prepared by dissolving any of saidcompounds in water containing an equivalent amount in moles of sodiumhydroxide and then freeze-drying the mixture. In this way, the desiredalkali metal salt of the spiro-hydantoin, spiro-thiazolidinedione,spiro-oxazolidinedione or spiro-succinimide can be prepared. In thosecases where the aromatic substituents contain carboxylic acid moieties(e.g., isopropanoic acid substituent), one equivalent of base will yieldthe corresponding sodium carboxylate salt. In such cases as theaforementioned, two mole equivalents will yield the disodium salt. Bythis method, the desired alkali metal salt is obtained as an amorphouspowder which is soluble in water.

In like manner, the potassium and lithium salts are analogouslyprepared, as are the alkali metal salts of all other spiro-tricyclecompounds of this invention which are reported in Examples I-XVII andXIX, respectively.

EXAMPLE XXII

The calcium salt ofspiro-(2-fluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione is prepared bydissolving said compound in water containing an equivalent amount inmoles of calcium hydroxide and then freeze-drying the mixture. Thecorresponding magnesium salt is also prepared in this manner, as are allother alkaline-earth metal salts not only of this particular compound,but also those spiro-tricyclic analogs previously described in ExamplesI-XVII and XIX, respectively.

EXAMPLE XXIII

The hydrogen chloride salt ofspiro-(7-fluoro-9H-indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione,spiro-(7-fluoro-5H-indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dioneor spiro-(7-fluoro-5H-indeno[1,2-b]-5,5'-thiazolidine)-2',4'-dione in1.0 to 1.5 equivalent amount of 1N to 10N hydrochloric acid and thenfreeze-drying the mixture in a manner to remove excess hydrochloricacid. By this method the aforementioned and related spiro-tricyclicazine analogs, previously described in Example XIX, and prepared ashydrogen chloride salt powders which are soluble in water.

EXAMPLE XXIV

A dry solid pharmaceutical composition is prepared by mixing thefollowing materials together in the proportions by weight specified:

    ______________________________________                                        Sprio-(2-fluoro-9,5'-thiazolidine)-2',4'-dione                                                          50                                                  Sodium Citrate            20                                                  Alginic Acid               5                                                  Polyvinylpyrrolidone      15                                                  Magnesium Stearate         5                                                  ______________________________________                                    

The dry composition is thoroughly blended, tablets are punched from theresulting mixture, each tablet being of such size that it contains 100mg of the active ingredient. Other tablets are also prepared in alikewise manner containing 10, 25 and 200 mg of active ingredient,respectively, by merely using an appropriate quantity by weight of thespiro-thiazolidinedione in each case. Likewise other related examples ofspiro-thiazoidinediones, spiro-imidazolidinediones,spiro-oxazolidinediones, spiro-succinimides can be formulated as tabletson a respective weight proportion.

EXAMPLE XXV

A dry solid pharmaceutical composition is prepared by combining thefollowing materials together in the weight proportions indicated below:

    ______________________________________                                        Spiro-(7-fluoro-5 .sub.-- H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-                                        50                                             2',5'-dione                                                                   Calcium Carbonate              20                                             Polyethylene glycol, Average Molecular Weight 25,000                                                         30                                             ______________________________________                                    

The dried solid mixture is thoroughly mixed until uniform incomposition. The powdered product is then used to fill soft elastic andhard-gelatin capsules so as to provide capsules containing 200 mg of theactive ingredient.

EXAMPLE XXVI

The following spiro-tricyclic compounds of the Examples and Preparationspreviously described were tested for their ability to inhibit or reducealdose reductase enzyme activity. The procedure for the aldose reductaseenzyme activity inhibition test is described in the followingpublications:

a) P. F. Kador, L. O. Merola and J. H. Kinoshita, Docum. Ophthal. Proc.Series, 18, 117-124 (1979);

b) P. F. Kador, J. H. Kinoshita, W. H. Tung and L. T. Chylack, Jr.,Invest. Ophthalmol. Vis. Sci., 19, 980-982 (1980);

c) P. F. Kador, D. Carper and J. H. Kinoshita, Analytical Biochemistry,114, 53-58 (1981).

Wherein the assay mixture used in the tests containing 0.1M potassiumphosphate buffer, pH 6.2, 0.2 mM nictoinamide adenine dinucleotidephosphate (NADPH), 10 mM D,L-glyceraldehyde, and an appropriate volumeof the enzyme preparation, thermostated at 25° C. in the cellcompartment of a spectrophotometer. These conditions are identical tothose published in references (a), (b) and (c), except that a largerNADPH concentration was employed. This insured a linear reaction ratefor longer time periods since one product of the reaction, NADP+,markedly inhibits the enzyme. The control sample contained no addedinhibitor. In order to measure aldose reductase inhibition activity,varying concentrations of the inhibitor examples set forth below wereadded to the standard incubation mixture. The control, containing theenzyme and NADPH, gave a very small, but measurable rate; thus, itserved as the blank against which to measure theglyceraldehyde-dependent rate of NADPH oxidation. The tests wereconducted with human placental aldose reductase enzyme. The results ofthe tests are the product of multiple assays. The IC50 data for eachcompound is expressed below in terms of concentration of compoundrequired to inhibit 50% human placental aldose reductase enzymeactivity. A test compound is considered active if it inhibits or reduceshuman aldose reductase activity at 1×10⁻⁴ M concentration or less. Thefollowing list is provided as a representative sample of the biologicalactivity of the spiro-tricyclic derivatives of the present invention.

A. d,1-Spiro-(2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione##STR163##

B. Spiro-(2,7-Difluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione##STR164##

C. d,1-Spiro-(2-fluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione##STR165##

D. Spiro-(2,7-difluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione##STR166##

E. d,1-Spiro-(5H-indeno[1,2-b]pyridine-5,3'-succinimide) ##STR167##

F. d,1-Spiro-(2-fluoro-9H-fluoren-9,3'-succinimide) ##STR168##

G. Spiro-(9H-fluoren-9,3'-succinimide) ##STR169##

H.d,1-Spiro-(2-chloro-7-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione##STR170##

I. d,1-Spiro-(9H-pyrrolol[1,2-a]indol-9,4'-imidazolidine-2',4'-dione##STR171##

J.d,1-Spiro-(7-nitro-5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione##STR172##

K.d,1-Spiro-(7-bromo-5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione##STR173##

L. d,1-Spiro-(2-chloro-9H-fluoren-9,4'imidazolidine)-2',5'-dione##STR174##

M. Spiro-(9H-fluoren-9,5'-thiazolidine)-2',4'-dione ##STR175##

N. Spiro-(9H-fluoren-9,5'-oxazolidine)-2',4'-dione ##STR176##

O. d,1-Spiro-(2-fluoro-9H-fluoren-9,5'-oxazolidine)-2',4'-dione##STR177##

P. d,1-Spiro-(9H-indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione##STR178##

Q. d,1-Spiro-(4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione##STR179##

R. d,1-Spiro-(8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione##STR180##

S. d,1-Spiro-(5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione##STR181##

Research (Kador, Merola and Kinoshite, Docum. Ophthal. Proc. Series, 18(1979) 117) has indicated that the evaluation of aldose reductaseinhibitors for potential human chemotherapy may require testing withhuman aldose reductase. There are species-linked differences in thesusceptibility for inhibition of aldose reductase. For example, rat lensaldose reductase behaves differently from human placental aldosereductase with respect to inhibition by synthetic chemical inhibitors.

EXAMPLE XXVII

According to the procedures of Kador, Merola and Kinoshite, Docum.Ophthal. Proc. Series, 18 (1979) 117 and Kador and Sharpless,Biophysical Chemistry, 8 (1978) 81 the inhibition exerted by examples ofthe present invention where evaluated against rat lens aldose reductase.Otherwise, the inhibitor assay is identical to that employed againsthuman aldose reductase in Example XXVI. Representative rat lens aldosereductase inhibition is presented in terms of the concentration of testcompound required to reduce rat lens aldose reductase enzyme activity by50%. A test compound is considered active if it inhibits or reduces ratlens aldose reductase activity at 1×10⁻⁴ M concentration or less.

A. Spiro-(2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione ##STR182##

B. Spiro-(2,7-difluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione##STR183##

C. Spiro-(2-fluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione ##STR184##

D. Spiro-(2,7-difluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione##STR185##

E. Spiro-(2-fluoro-9H-fluoren-9,3'-succinimide) ##STR186##

F. Spiro-(9H-fluoren-9,5'-thiazolidine)-2',4'-dione ##STR187##

G. Spiro-(2-methylthio-9H-fluoren-9,4'-imidazolidine)-2',5'-dione##STR188##

H. Spiro-(5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione##STR189##

I. Spiro-(2-fluoro-9H-fluoren-9,5'-oxazolidine)-2',4'-dione ##STR190##

J. Spiro-(5H-indeno[1,2-b]pyridine-5,3'-succinimide) ##STR191##

K. Spiro-(8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione##STR192##

EXAMPLE XXVIII

Aldose reductase inhibitor potency may be evaluated in rat lens cultureassays where 30 mM of glucose, galactose or xylose can be used inculture to induce a `sugar` cataract. In addition to monitoring lensclarity, certain biochemical radiolabeled markers (e.g., choline --³ Hand ⁸⁶ Rb) are employed to measure lens function. See Obazawa, Merolaand Kinoshita, Invest. Ophthalmol., 13 (1974) 204 and Jernigan, Kadorand Kinoshita, Exp. Eye Res., 32 (1981) 709.

In the present case, the 30 mM xylose cataract model was selectedbecause 30 mM xylose is more effective in product `sugar` cataracts thaneither 30 mM glucose or 30 mM galactose. The general procedure is asfollows: a) Sprague-Dawley rats of 75-100 g body weight are sacrificedand the lenses removed immediately; b) the contralateral lens of thepair of lenses is employed as untreated control lens; c) the test lensis cultured in TC-199 culture media in the presence of 30 mM xylose, 30mM xylose plus a selected concentration of test compound or a selectedconcentration of test compound; d) the contralateral control lens istreated identical to the test lens except no test compound or xylose isincluded; e) the matched lens pairs are cultured for 18 h in a CO₂incubator; f) the lenses are compared morphologically and weighed. Alllenses, control and test groups, are allowed to preincubate for 1 h inrespective control media or drug control media prior to transfer toxylose media or xylose-drug media. In those cases where radiolabelledmarkers are to be measured, the lenses are treated as aforementionedexcept the radiolabelled marker(s) are added to the culture at fourhours before harvesting. Radiolabelled markers include choline --³ H([methyl-¹⁴ C]-choline chloride available from New England Nuclear),AIBA --¹⁴ C (α-[1-¹⁴ C]-(CH₃)₂ C(NH₂)COOH available from New EnglandNuclear) and ⁸⁶ Rb. The effect of xylose on lens uptake of ⁸⁶ Rb, lensuptake of amino acid (AIBA --¹⁴ C) and lens uptake of choline --³ H andthe effectiveness of representative compounds of the present inventionto preserve normal lens morphology is reported here.

The effect of 30 mM xylose and 30 mM xylose plus selected concentrationsof test compound on radioactivity ratio is expressed as L/M % ofcontrol. L/M % of control is defined as the test lens radioactivitydivided by culture media radioactivity as a percentage of the controlcontralateral lens radioactivity to media radioactivity ratio underidentical test conditions but always without xylose or test compound inthe control. The effect of 30 mM xylose in the culture media gives areproducible deleterious effect on the lens as measured by the variousL/M %. Furthermore, after incubation of the lens in 30 mM xylose in theTC-199 culture media, the lens gains 20% weight (mostly water weightincrease based on dry lens weight measurements) and becomes opaque inthe cortex of the lens. Each experiment requires 20-40 pairs of lensesto determine the potency of a selected aldose reductase inhibitor.

For comparison purposes, representative examples of the presentinvention will be profiled in the following table against examples fromU.S. application Ser. Nos. 368,630 and 368,631.

REPRESENTATIVE COMPOUNDS EVALUATED

A. Spiro-(-2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione;

B. Spiro-(2,7-difluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione;

C. Spiro-(2-fluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione;

D. Spiro-(2,7-difluoro-9H-fluoren-9,5'-thiazolidine)-2',4'-dione.

    ______________________________________                                        Radiolabel Uptake-L/M% Table                                                              (1)         (2)     (3)                                           Compound*   L/M%        L/M%    L/M%                                          ______________________________________                                        None        47          33      45                                            A           73          50      55                                            B           105         87      82                                            C           77          58      70                                            D           109         85      83                                            ______________________________________                                         *Compound concentration 7.5 × 10.sup.-7 M in culture media.             (1) L/M% = Lens uptake of choline .sup.-3 H after 18 h 30 mM xylose           culture.                                                                      (2) L/M% = Lens uptake of AIBA .sup.-14 C (amino acid) after 18 h 30 mM       xylose culture.                                                               (3) L/M% = Lens uptake of .sup.86 Rb after 18 h 30 mM xylose culture.    

In all cases Compounds A, B, C and D prevented lens opacification andlens wet weight increase at compound concentration of 7.5×10⁻⁷ M in theculture media.

Compound A and B according to U.S. application Ser. Nos. 368,360 and368,631 are wholly effective in preventing cataract in galactosemic ratswhen administered per oral by gauge once a daily at 1.26 and 0.4 mg/kgrespectively. In another efficacy study reported in the sameapplications, Compound A was found to prevent cataract and significantlypreserve motor nerve conduction velocity in chronicstreptozotocin-induced rats at 8 mg/kg per oral per day.

The following Examples XXIX-XXXVIII are presented to further illustratemethods for synthesizing certain preferred species of the presentinvention.

EXAMPLE XXIX General Procedure for the Synthesis of2,4,7-Trifluoro-5-Methylthiospiro[9H-Fluorene-9,4'-Imidazolidine]-2',5'-Dione##STR193## 2,4,7-Trifluoro-5-nitrofluorene was oxidized to thefluorenone using sodium dichromate in acetic acid and then reduced to5-amino-2,4,7-trifluorofluorenone using tin(II)chloride in a mixture ofethanol and concentrated hydrochloric acid. The amine was converted tothe 5-diazonium tetrafluoroborate salt by treatment with sodium nitritein a mixture of tetrahydrofuran and aqueous fluoboric acid. The materialwas allowed to react with potassium ethyl xanthate in a hot mixture ofwater and toluene to provide ethyl 2,4,7-trifluoro-9-oxofluoren-5-ylxanthate which was then hydrolyzed using ethanolic sodium hydroxide andS-methylated with methyl iodide to give2,4,7-tri-fluoro-5-methylthiofluorenone. Hydantoin formation wasaccomplished by heating an ethanol solution of the ketone, potassiumcyanide, ammonium carbonate at 115° C. for 15 hours. EXAMPLE XXX GeneralProcedure for the Synthesis of2,4,7-Trifluoro-5-Methylspiro[9H-Fluorene-9,4'-Imidazolidine]-2',5'-Dione##STR194## Treatment of 2,7-difluoro-4-methyl-9H-fluorenone in aceticacid with a mixture of nitric acid and sulfuric acid gave2,7-difluoro-4-methyl-5-nitro-9H-fluorenone as the major product.5-Amino-2,7-difluoro-4-methyl-9H-fluorenone was obtained by reductionusing tin(II)chloride in a mixture of ethanol and aqueous hydrochloricacid. Thermal decomposition in hot xylene of the diazoniumtetrafluoroborate, formed with sodium nitrite in aqueous fluoboric acid,provided 2,4,7-tri-fluoro-5-methyl-9H-fluorenone. Treatment of theketone with potassium cyanide and ammonium carbonate in ethanol at 120°C. for 18 hours provided the title compound. EXAMPLE XXXI The Synthesisof2,4,7-Trifluoro-5-Methoxyspiro(9H-Fluorene-9,4'-Imidazolidine)-2',5'-Dione##STR195## 2,4,7-Trifluoro-5-methoxy-9H-fluorene

A solution of 5-amino-2,4,7-trifluoro-9H-fluorene (10.0 g, 0.042 mol) in30 mL of tetrahydrofuran was added to 100 mL of 6M aqueous sulfuricacid. This solution was cooled to 0° C. and sodium nitrite (1.1 eq,0.046 mol, 3.3 g), dissolved in small volume of water, was slowly added.After having stirred at 5° C. for 1 h, the mixture was added dropwise to100 mL of 3M aqueous sulfuric acid at 100° C. The resulting mixture washeated at 100° C. for an additional 10 min, allowed to cool, andextracted with ethyl acetate. The ethyl acetate extracts were dried overMgSO₄ and concentrated to leave 10 g of a dark oil which was dissolvedin a mixture of 15 mL tetrahydrofuran and 100 mL of 2M aqueous sodiumhydroxide. The solution was heated to 40° C. and dimethyl sulfate (1 eq,5.2 g, 4.1 mL) was added slowly. After the addition was complete, thesolution was heated to 50° C. and another 0.5 eq of dimethyl sulfate wasadded. After 1 h at 50° C., the solution was cooled to room temperatureand extracted with 50 mL of ethyl acetate. The ethyl acetate extract waswashed with water and brine, dried over MgSO₄, and concentrated to leave9.0 g of a dark solid which was chromatographed on silica gel using 20%ethyl acetate in hexane to provide 4.8 g (45%) of the fluorene.

2,4,7-Trifluoro-5-methoxy-9H-fluoren-9-one

Sodium dichromate dihydrate (2 eq, 0.26 mol, 7.9 g) was added to asolution 2,4,7-trifluoro-5-methoxy-9H-fluorene (3.3 g, 0.013 mol) in 100mL of acetic acid and the mixture was refluxed for 5 h. The cooledreaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate extract was washed with saturated aqueous sodiumbicarbonate and water, dried over MgSO₄, and concentrated to leave 3 gof a yellow solid which was chromatographed on silica gel using 15%ethyl acetate in hexane to provide 2.0 g (57%) of the fluorenone: mp164°-166° C.

2,4,7-Trifluoro-5-methoxyspiro(9H-fluorene-9,4'-imidazolidine)2',5'dione

A mixture of 2,4,7-trifluoro-5-methoxy-9H-fluoren-9-one (2.0 g, 7.6mmol), potassium cyanide (3 eq, 23 mmol, 1.5 g), and ammonium carbonate(4 eq, 30 mmol, 2.9 g) in 50 mL of ethanol was heated in a sealed bombat 115° C. for 24 h. After the bomb was cooled and opened, the solventwas evaporated and the residue dissolved in 1M aqueous sodium hydroxide.The basic solution was extracted with ethyl acetate to remove baseinsoluble impurities and then acidified using concentrated hydrochloricacid. The acidic solution was extracted with ethyl acetate and theextracts were dried over MgSO₄ and concentrated to leave 1.2 g of abrown solid. Chromatography on silica gel using 45% ethyl acetate inhexane provided 500 mg (20%) of the spirohydantoin: mp 227°-229° C.

Analysis calculated for C₁₆ H₉ F₃ N₂ O₃ : C,57.49; H, 2.71; N, 8.38.Found: C,57.68; H, 2.81; N, 8.34.

EXAMPLE XXXII Synthesis of 2,4,5,7-Tetrafluorospiro(9H-fluorene-9,4'-imidazolidine-2',5'-dione

Experimental details for the four-step synthesis of2,4,5,7-tetrafluorospiro (9H-fluorene-9,4'-imidazolidine-2',5'-dionefrom 3,5-difluorobromobenzene are provided. Also included is a procedurefor the preparation of palladium acetate from the palladium metal whichis recovered from the last step and recycled. ##STR196##

3,3'5,5'-Tetrafluorodiphenylcarbinol

A 22-L flask equipped with a mechanical stirrer, a 2-L addition funnel,an efficient condenser, and a bottom drain was dried under a stream ofdry nitrogen overnight and then charged with magnesium turnings (90.1 g,3.70 mol) and anhydrous ether (2 L). A portion (200 mL) of a solution of3,5-difluorbromobenzene (650.0 g, 3.37 mol) (Note 1) in 1500 mL of etherwas added and the mixture was heated to reflux. A small amount (˜3 g) ofdifluorophenylmagnesium bromide (prepared in a test tube) was added toinitiate the reaction. When the reaction mixture turned gray and cloudy,the heating mantle was turned off as the exothermic reaction maintainedreflux temperature. Shortly afterwards the mixture turned brown and avigorous reaction set in. After this subsided, the remainingdifluorobromobenzene solution was added at a rate which maintained asteady reflux (required 2 hrs) (Note 2). After the addition wascomplete, the mixture was refluxed for 30 min before the heat was turnedoff and a solution of ethylformate (125.0 g, 1.69 mol) in ether (1.5 L)was added at a rate that maintained a gentle reflux. The mixture wasthen refluxed for another hour before it was quenched by the addition of6 L of 20% aqueous hydrochloric acid. The aqueous layer was removed andthe organic layer was washed twice with water, dried over MgSO₄,filtered, and concentrated to leave 427 g of a dark brown, viscous oil.The oil was distilled using a short path, large bore distillationapparatus to provide 217 g (50%) of a pale yellow solid (Notes 3 and 4):bp 108°-115° C./0.06 mmHg; mp 61°-64° C.; MS m/z 256 (M+), 141 (basepeak); ¹ H NMR (CDCl₃) δ6.82-6.42 (m, 6); 5.62 (d, 1); 2.18 (d, 1); IR(KBr) 3300 (broad), 1615, 1592, 1115 cm⁻¹.

Notes

1. The 3,5-difluorobromobenzene was purchased from Yarsley ChemicalCompany.

2. In order to avoid an uncontrollable reaction, it is essential thatthe grignard reaction be well established (as evidenced by the formationof the brown color) before a large volume of aryl bromide is added.

3. At the expense of yield, colorless material can be obtained by a morecareful distillation.

4. Subsequent oxidation attempts using the crude alcohol resulted in aproduct which was very difficult to isolate and purify.

3,3',5,5'-Tetrafluorobenzophenone

In a 22-L flask equipped with a mechanical stirrer and thermometer,3,3',5,5'-Tetrafluorodiphenylcarbinol (404 g, 1.58 mol) was dissolved in3 L of glacial acetic acid. Sodium dichromate dihydrate (471 g, 1.58mol) was added in one portion, forming a dark brown solution and anexothermic reaction which caused the temperature to rise to 60° C.within 30 min and maintained that temperature for 15 min. When thetemperature began to fall, TLC analysis indicated that the reaction wascomplete (Note 1). Water (˜10 L) was added to the reaction and theprecipitate was collected by filtration, washed with water until thewashings were colorless, and dried in the funnel. The white solid wasthen dissolved in ethyl acetate (˜4 L), washed with water (2×2.5 L),dried over MgSO₄, filtered, and evaporated to dryness to provide 358 g(89%) of the ketone which was used in the next step without furtherpurification: mp 84°-87° C.; MS m/z 254 (M+); ¹ H NMR (CDCl₃) δ7.28-6.80(m, 6); IR (KBr) 3080, 1670, 1582, 1115, 975, 745 cm⁻¹.

Note

1. A sample was added to water and extracted with ethyl acetate. Theethyl acetate solution was spotted on a silica gel plate and developedusing 20% ethyl acetate/hexane. The R_(f) of the starting material is0.6 while that of the product is 0.8.

5,5-Di(3,5-difluorophenyl)-2,4-imidazolidinedione

A mixture of 3,3',5,5'-tetrafluorobezophenone (358 g, 1.41 mol),potassium cyanide (137.5 g, 2.11 mol), ammonium carbonate (406 g, 4.22mol) and ethanol (3.5 L) was heated at 115° C. for 16 h in a stirred 2gal pressure reactor. After chilling to relieve the pressure, thereactor was opened and the mixture was poured into 8 L of water in a22-L flask equipped with a mechanical stirrer. The mixture was acidified(pH 2.0) using concentrated hydrochloric acid (˜1 L) (Note 1) and theresulting precipitate was collected by filtration, washed with water,and pressed dry. The crude material was recrystallized from ethanol (˜6L) to provide 399.5 g (87%) of5,5-di(3,5-difluorophenyl)-2,4-imidazolidinedione (Note 2): mp 271°-274°C.; MS m/z 324 (M+); ¹ H NMR (DMSO-d₆) δ9.50 (s, 2); 7.42-6.90 (m, 6);IR (KBr) 3265, 3160, 3060, 1762, 1710 cm⁻¹.

Analysis calcd. for C₁₅ H₈ F₄ N₂ O₂ : C, 55.57; H, 2.49; N, 8.64. Found:C, 55.55; H, 2.38; N, 8.62.

1. This step should be carried out cautiously in an efficient hood sincehydrogen cyanide is formed. The acidification is done slowly to controlthe vigorous foaming.

2. Recrystallization of the product simplifies the work-up procedure ofthe following reaction.

2,4,5,7-Tetrafluorospiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione

A solution of 5,5-di(3,5-difluorophenyl)-2,4-imidazolidinedione (240 g,0.74 mol) and palladium(II) acetate (167.8 g, 0.748 mol) in 2.4 L of a50% mixture (v/v) of glacial acetic acid and 69%-72% perchloric acid ina 5-L flask equipped with a mechanical stirrer and a thermometer washeated at 120° to 135° C. for 1.5 h. The reaction mixture was filteredhot through a fritted glass funnel and the black palladium metal waswashed well with hot acetic acid. the combined filtrate and washingswere poured into 10 L of water and the precipitate was collected byfiltration, washed with water, and dried in the funnel. The crude solidwas then dissolved in boiling acetonitrile, treated with decolorizingcarbon, filtered through celite, and concentrated to 3 L. The solutionwas slowly cooled to room temperature and then in the refrigerator asthe product crystallized. The white crystals were collected byfiltration, washed with acetonitrile, and dried to provide 167 g (70%)of 2,4,5,7-tetraflourospiro (9H-fluorene-9,4'-imidazolidine-2',5'-dione.A second recrystallization gave 150 g of pure compound: mp 287°-290° C.;MS m/z 322 (M+), 251 (base peak); ¹ H NMR (DMSO-d₆)δ8.73 (s, 2),7.52-7.49 (m, 4); IR (KBr) 3340-3160 (broad), 1772, 1722, 1122 cm⁻¹.

Anal. calcd. for C₁₅ H₆ F₄ N₂ O₂ : C, 55.91; H, 1.88; N, 8.69; Found: C,55.65; H, 1.96; N, 8.70.

EXAMPLE XXXIII The Synthesis of2,4,5,7-Tetrafluorospiro(9H-fluorene-9,5'-thiazolidine)-2',4'-dione

Experimental details for the four step synthesis of2,4,5,7-Tetrafluorospiro(9H-fluorene-9,5'-thiazolidine)-2',4'-dione from2,4,5,7-tetrafluorofluorene are provided. ##STR197##

Methyl 2,4,5,7-Tetrafluorofluorene-9-carboxylate

Under nitrogen, n-butyllithium (5.6 mL of a 2.5M hexane solution) wasadded dropwise, to a -78° C. solution of the 2,4,5,7-tetrafluorofluorenein gold label THF (80 mL) over 2 min. After 20 min, the mixture waspoured onto a slurry of dry-ice (10 g) in anhydrous ether. The solventswere evaporated and the residue was dissolved in methanol (200 mL) andacidified with acetyl chloride (5 mL). After stirring for 18 h, thereaction was concentrated and the residue was diluted with saturatedaqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate(3×100 mL). The combined organics were washed with brine (3×100 mL),dried (MgSO₄), and evaporated. The residue was chromatographed on silicagel using petroleum ether to provide 2.1 g (57%) of product: ¹ H NMR(DMSO-d₆, 200 MHz) δ7.44 (dd, 2H, J=2.2 and 8.3 Hz), 7.40-7.25 (m, 2H),5.37 (s, 1H), 3.76 (s, 3H).

Methyl 9-Chloro-2,4,5,7-tetrafluorofluorene-9-carboxylate

A solution of methyl 2,4,5,7-tetrafluorofluorene-9-carboxylate (1.49 g,5.03 mmol) in dry THF (15 mL) was added over 14 min to a stirred, roomtemperature suspension of unwashed sodium hydride (1.25 eq, 6.29 mmol,250 mg of a 60% oil dispersion) in THF (15 mL). The mixture was thencooled in an ice water bath and after 9 min a solution ofN-chlorosuccinimide (1.2 eq, 6.04 mmol, 810 mg) was added over 14 min.After slowly warming to room temperature, the mixture was stirred for 21h before it was poured into 100 mL of water and extracted with ethylacetate. The extracts were washed with aqueous sodium carbonate, aqueoussodium bisulfate, and brine, dried (MgSO₄), and concentrated to leave1.4 g of crude material. Chromatography on silica gel using 20% ethylacetate in hexane provided 970 mg (58%) of nearly pure material: ¹ H NMR(CDCl₃) δ7.20 (dd, 2H), 7.0-6.6 (m, 2H), 3.75 (s, 3H); IR (KBr) 1730,1600, 1580, 1410, 1105 cm⁻¹ ; MS m/z 330 (M+), 271 (base peak).

2,4,5,7-Tetrafluorospiro(9H-fluorene-9,5'-thiazolidine)-2'-imino-4'-one

A mixture of methyl 9-chloro-2,4,5,7-tetrafluorofluorene-9-carboxylate(970 mg, 2.94 mmol), thiourea (1.1 eq, 3.23 mmol, 250 mg), and sodiumacetate (0.75 eq, 2.20 mmol, 180 mg) in acetic acid (8 mL) was refluxedfor 8 h. The mixture was cooled to room temperature and the precipitatewas collected by filtration, washed with acetic acid and ether, and airdried to provide 440 mg of crude material: MS m/e 338 (M+), 268 (basepeak).

2,4,5,7-Tetrafluorospiro(9H-fluorene-9,5'-thiazolidine)-2',4'-dione

Crude2,4,5,7-tetrafluorospiro(9H-fluorene-9,5'-thiazolidine)-2'-imino-4'-one(440 mg) was refluxed in a mixture of 8 mL each of methanol andconcentrated hydrochloric acid for 4 h. After the mixture cooled to roomtemperature, 8 mL of water was added and the white solid was collected,washed with cold water, and dried to provide 180 mg of crude product.Chromatography on silica gel using a gradient of 1% to 10% methanol inchloroform provided 90 mg of the thiazolildine dione: ¹ H NMR (DMSO-d₆,200 MHz) δ7.78 (dd, 2H, J=2.2 and 8.0 Hz), 7.52-7.41 (m, 2H); IR (KBr)1750, 1700 cm⁻¹ ; MS m/z 339 (M+), 268 (base peak).

Anal. calcd for C₁₅ H₅ F₄ NO₂ S: C, 53.10; H, 1.49; N, 4.13. Found: C,52.88; H, 1.58; N, 4.00.

EXAMPLE XXXIV The Preparation of2,7-Difluoro-3-Methylspiro(9H-Fluorene-9,4'-Imidazolidine)-2',5'-Dione##STR198## Methyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoate

A mixture of 4-fluoro-3-methylphenylboronic acid (6.5 g, 42.5 mmol),methyl 2-bromo-5-fluorobenzoate (10.0 g, 42.9 mmol), tetrakis(triphenylphosphine) palladium(O) (1.0 g, 0.87 mmol, 0.2 eq), toluene(100 mL), 2M aqueous sodium carbonate (50 mL) and ethanol (25 mL) wasrefluxed for 9 h. The reaction mixture was then poured into 50 mL eachof concentrated ammonium hydroxide, 2M aqueous sodium carbonate, andwater, the organic phase was separated, and the aqueous was extractedwith ethyl acetate. The combined organics were washed with brine, driedover MgSO₄, and concentrated to leave an oil which was chromatographedon silica gel using hexane to provide 11 g (98%) of the ester.

Methyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoic acid

Potassium hydroxide (6 g) and water (50 mL) were added to a solution ofmethyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoate (10.2 g, 40.0 mmol)in methanol (150 mL) and the mixture was stirred at room temperature for18 h. The reaction mixture was then evaporated to near dryness,acidified with 1N aqueous hydrochloric acid, and extracted with ethylacetate. The combined extracts were washed with brine, dried over MgSO₄,and concentrated to leave a residue which was chromatographed on silicagel using 30% ethyl acetate in hexane to provide 9.7 g of the acid.

2,7-Difluoro-3-methyl-9H-fluorenone

A stirred mixture of methyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoicacid (6.5 g, 26.2 mmol) and polyphosphoric acid (30 g) was heated at180° C. for 2 h. After the mixture had cooled to 80° C., it was pouredinto water (200 mL), and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over MgSO₄, treated withcharcoal, and concentrated. Chromatography on silica gel using 20%toluene in hexane provided 2 g (33%) of the desired ketone.

2,7-Difluoro-3-methylspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione

A mixture of 2,7-difluoro-3-methyl-9H-fluorenone (1.8 g, 7.8 mmol),potassium cyanide (2.0 g, 31.2 g, 4 eq), and ammonium carbonate (2.2 g,23.4 mmol, 3 eq) in 60 mL of ethanol was heated in a sealed bomb at 115°C. for 24 h. The cooled bomb was opened, and the excess potassiumcyanide was destroyed with 1M aqueous hydrochloric acid. The mixture wasthen partitioned between 1M aqueous sodium hydroxide (150 mL) and ethylacetate (200 mL) and the basic aqueous phase was removed. The organicphase was extracted with 1M sodium hydroxide and the combined basicphases were acidified and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over MgSO₄, and concentrated. Theresidue was recrystallized from ethanol/water to provide 290 mg of purehydantoin: mp>315° C.

Analysis calculated for C₁₆ H₁₀ F₂ N₂ O₂ : C, 64.00; H, 3.36; N, 9.33.Found: C, 64.05; H, 3.35; N, 9.35.

EXAMPLE XXXV Synthesis of2,7-Difluoro-4-methylspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione

The preparation of2,7-difluoro-4-methylspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dionefrom ethyl 2-(2-methyl-4-fluorophenyl)-5-fluorobenzoate is described.##STR199##

Ethyl 2-(2-Methyl-4-fluorophenyl)-5-fluorobenzoate

Tetrakis(triphenylphosphine)palladium(O) (0.02 eq, 0.31 g) was added toa vigorously stirred solution of ethyl 2-bromo-5-fluorobenzoate (1.0 eq,3.3 g, 0.013 mol) and 2-methyl-4-fluorophenylboronic acid (1.2 eq, 0.016mol, 2.4 g) in 45 mL of toluene, 22 mL of 2M aqueous sodium carbonate,and 11 mL of ethanol and the mixture was refluxed for 9 h. The cooledreaction mixture was poured into 50 mL each of water, ammoniumhydroxide, and 2M aqueous sodium bicarbonate and then filtered throughCelite. The filtrate was extracted with ethyl acetate and the organicswere dried (MgSO₄) and concentrated to yield 3.9 g of a yellow oil.Chromatography (silica gel, 20% ethyl acetate/hexane) gave 3.4 g (92%)of product as a light colored oil. ¹ H NMR (CDCl₃, 60 mHz) δ7.7 (dd,1H), 7.5 (m, 1H), 7.25-6.75 (m, 4 H), 4.0 (q, 2H), 2.0 (s, 3H), 1.0 (t,3H); IR (CDCl₃ solution) 3130, 2220, 1700, 1450, 1080 cm⁻¹ ; MS m/z 276(M+), 201 (base peak).

2-(2-Methyl-4-fluorophenyl)-5-fluorobenzoic acid

A solution of methanol (25 mL), water (10 mL), potassium hydroxide (2eq, 1.2 g), and ethyl 2-(2-methyl-4-fluorophenyl)-5-fluorobenzoate (1.0eq, 3.4 g) was allowed to stir at room temperature for 16 h. Thereaction was then concentrated in vacuo and the residue dissolved in 20mL of water. Acidification with concentrated hydrochloric acid resultedin the precipitation of the product as a white solid. The solid wascollected by filtration, dissolved up in ethyl acetate, washed withwater, and then dried over magnesium sulfate. Concentration of the ethylacetate solution left 3.2 g of product as a white solid. MS m/z 248(M+), 201 (base peak).

2,7-Difluoro-4-methyl-9-fluorenone

2-(2-Methyl-4-fluorophenyl)-5-fluorobenzoic acid (3.2 g, 0.013 mol) wasplaced in 40 g of polyphosphoric acid and heated at 210° C. for 1.5 h.The reaction was allowed to cool and was then poured into 200 mL of icewater. Ethyl acetate and 1N aqueous sodium hydroxide (100 mL each) wereadded and the solution was filtered through celite. The organic layerwas separated and the aqueous layer was extracted once again with 75 mLof ethyl acetate. The combined organics were washed with saturatedaqueous sodium bicarbonate and water, dried (MgSO₄), and concentrated invacuo leaving 1.9 g of product as a yellow solid. Recrystallization fromethanol gave 1.5 g (52%) of pure product: mp 172°-175° C.; ¹ H NMR(CDCl₃, 60 mHz) δ7.6-6.7 (m, 5H), 2.5 (s, 3H); IR (KBr) 1700, 1460,1280, 775 cm⁻¹ ; MS m/z 230 (M+). Analysis Calculated for C₁₄ H₈ OF₂ :C, 73.04; H, 3.50. Found: C, 72.93; H, 3.67.

2,7-Difluoro-4-methylspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione

2,7-Difluoro-4-methyl-9-fluorenone (1.3 g, 0.0056 mol), potassiumcyanide (3 eq, 0.017 mol, 1.1 g), ammonium bicarbonate (3 eq, 0.017 mol,1.3 g), and 50 mL of ethanol were placed in a sealed bomb and heated at125° C. for 20 h. The bomb was cooled to room temperature and thecontents were filtered through Celite washing with water and ethylacetate. The filtrate was concentrated in vacuo and the residue wasdissolved in 40 mL of 1N aqueous sodium hydroxide and washed with ethylacetate (2×30 mL). The aqueous solution was acidified with concentratedhydrochloric acid and the product extracted into ethyl acetate. Theorganic solution was then dried and concentrated providing 1.1 g of acrude white solid which was recrystallized from ethanol to give 340 mgof2,7-difluoro-4-methylspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione:mp>320° C.; ¹ H NMR (DMSO-d₆, 60 mHz) δ8.5 (s, 1H), 7.8 (m, 1H), 7.2 (m,4H), 2.7 (s, 3H); IR (KBr) 3300, 1710, 1380, 770 cm⁻¹ ; MS m/z 300 (M+),229 (base peak). Analysis Calculated for C₁₆ H₁₀ F₂ N₂ O₂.1/2H₂ O: C,62.14; H, 3.58; N, 9.06. Found: C, 62.21; H, 3.58; N, 8.81.

EXAMPLE XXXVI Synthesis of2,7-Difluoro-4-methoxyspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione

The preparation of2,7-Difluoro-4-methoxyspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dionefrom 2,7-difluoro-4-aminofluorene is described. ##STR200##

2,7-Difluoro-4-methoxy-9H-fluorene

A solution of 2,7-difluoro-4-amino-9H-fluorene, (10 g, 0.046 mol) in 20mL of tetrahydrofuran was added to 100 mL of 6M aqueous sulfuric acid.This yellow solution was cooled to 0° C. and sodium nitrite (1.0 eq, 3.6g), dissolved in a small volume of water, was slowly added. Thetemperature was kept below 5° C. throughout the addition and was kept at0° C. for 1 h afterward. The reaction was then added to a 100° C. 3Maqueous sulfuric acid solution. The temperature of the hot acid solutionwas controlled by the rate of addition and was not allowed to go below85° C. After complete addition, the reaction was stirred for 2 minutesat 100° C. and then allowed to cool to room temperature. The aqueoussolution was extracted with ethyl acetate (2×20 mL) and the combinedextracts were dried (MgSO₄), filtered through a small pad of silica gel,and concentrated in vacuo. The residue was dissolved in 100 mL of 2Naqueous sodium hydroxide and heated to 45° C. Dimethyl sulphate (1.0 eq,4.5 mL) was then added dropwise. The solution was kept basic and at 45°C. throughout the addition. Another portion of dimethyl sulphate (0.5eq., 2.3 mL) was added and the solution was heated to 50° C. for 30minutes. The cooled solution was extracted with ethyl acetate (2×50 mL)and the extracts were dried (MgSO₄), treated with carbon, filtered, andconcentrated to give a crude black solid. The solid was stirred in 500mL of hexane and the insoluble material filtered off. Concentration ofthe hexane solution gave 6.8 g of a crude yellow solid. Chromatography(silica gel, 10% ethyl acetate in hexane) gave 6.3 g (58%) of product asa yellow crystalline solid: ¹ H NMR (CDCl₃, 60 MHz) δ7.9 (dd, 1H),7.2-6.3 (m, 4H), 3.9 (s, 3H), 3.7 (s, 2H); IR (KBr) 1590, 1450, 1120,830 cm⁻¹ ; MS m/z 232 (M+).

2,7-Difluoro-4-methoxy-9H-fluorenone

2,7-Difluoro-4-methoxy-9H-fluorene (4 g, 0.017 mol), sodium dichromatedihydrate (1.1 eq, 5.7 g) and 50 mL of acetic acid were heated to 50° C.for 1 h. No change was observed on TLC (30% ethyl acetate/hexane) so thetemperature was raised to 75° C. and held there for 3 h. The reactionwas then poured into water and extracted with ethyl acetate. The organicsolution was washed with aqueous sodium bicarbonate, dried (MgSO₄), andconcentrated in vacuo to give 3.8 g of a yellow solid. Recrystallizationof the solid from ethanol gave 1.1 g of pure product. (The rest of thematerial was identified as starting material): ¹ H NMR (CDCl₃, 60 MHz)δ7.5 (dd, 1H), 7.2-6.6 (m, 4H), 3.9 (s, 3H); IR (KBr) 1700, 1450, 1300,780 cm⁻¹ ; MS m/z 246 (M+).

2,7-Difluoro-4-methoxyspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione

2,7-Difluoro-4-methoxy-9H-fluorenone (1.1 g, 0.004 mol), potassiumcyanide (1.5 eq, 0.007 mL, 0.44 g), ammonium carbonate (3.0 eq, 0.014mol, 1.3 g) and 25 mL of ethanol were placed in a sealed bomb and heatedat 115° C. for 24 h. The cooled reaction mixture was poured into aboiling flask and concentrated in vacuo. The residue was dissolved inethyl acetate and the solution was washed with 1N aqueous hydrochloricacid, treated with carbon, dried (MgSO₄), filtered, and concentrated togive 1.5 g of an off-white solid. The solid was dissolved in 1N aqueoussodium hydroxide, filtered through Celite, and acidified withconcentrated hydrochloric acid. The white precipitate was collected andrecrystallized from ethanol. The still impure product waschromatographed (silica gel, 10% acetone/hexane) to give 300 mg of pure2,7-difluoro-4-methoxyspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione:1H NMR (CDCl₃, 200 MHz) δ11.3 (s, 1H, exchangeable), 8.66 (s, 1H,exchangeable), 7.88 (dd, 1H, J=5.2 and 8.5 Hz), 7.44 (dd, 1H, J=2.3 and8.5 Hz), 7.29 (ddd, 1H, J=2.5, 8.5, and 9.5 Hz), 7.08 (dd, 1H, J=2.1 and11.6 Hz), 7.03 (dd, 1H, J=2.1 and 8.0 Hz), 3.98 (s, 3H); IR (KBr) 1700,1450, 1190, 830 cm⁻¹ ; MS m/z 316 (M+), 71 (base peak). Analysiscalculated for C.sub. 16 H₁₀ F₂ N₂ O₃ : C, 60.76; H, 3.19; N, 8.86.Found: C, 60.65; H, 3.19; N, 8.86.

EXAMPLE XXXVII Synthesis of3,7-Difluoro-9-methylspiro[5H-indeno[1,2-b]pyridine-5,4'-imidazolidine]-2',5'-dione

The four-step synthesis of3,7-Difluoro-9-methylspiro[5H-indeno[1,2-b]pyridine-5,4'-imidazolidine]-2',5'-dionefrom ethyl 2-(2-methyl-4-fluorophenyl)-5-fluoro-3-pyridinecarboxylate isdescribed. ##STR201##

Ethyl 2-(2-methyl-4-fluorophenyl)-5-fluoro-3-pyridinecarboxylate

Tetrakis(triphenylphosphine)palladium(O) (0.02 eq, 0.89 g) was added toa vigorously stirred solution of ethyl2-chloro-5-fluoro-3-pyridinecarboxylate (0.038 mol, 7.8 g) and2-methyl-4-fluorophenylboronic acid (1.5 eq, 0.057 mol, 8.9 g) in 100 mLof toluene, 50 mL of 2M aqueous sodium carbonate, and 25 mL of ethanoland the mixture was refluxed for 9 h. The cooled reaction mixture waspoured into 100 mL each of water, ammonium hydroxide, and 2M aqueoussodium carbonate and then filtered through Celite. The filtrate wasextracted with ethyl acetate and the organics were dried (MgSO₄) andconcentrated to yield 12 g of a red oil. Chromatography (silica gel, 20%ethyl acetate/hexane) gave 9.7 g (92%) of product as a light coloredoil: ¹ H NMR (CDCl₃, 60 MHz) δ8.7 (d, 1H), 8.0 (dd, 1H), 7.1-6.8 (m,3H), 4.1 (q, 2H), 2.0 (s, 3H); MS m/z 277 (M+).

2-(2-Methyl-4-fluorophenyl)-5-fluoro-3-pyridinecarboxylic Acid

A solution of methanol (100 mL), water (10 mL), potassium hydroxide (2eq, 4.0 g), and ethyl2-(2-methyl-4-fluorophenyl)-5-fluoro-3-pyridinecarboxylate (1.0 eq, 9.6g) was allowed to stir at room temperature for 16 h. The reaction wasthen concentrated in vacuo and the residue dissolved in 80 mL of water.Acidification with concentrated hydrochloric acid did not result inprecipitation of product so the product was extracted out with ethylacetate. Drying (MgSO₄) and concentration of the organics left 8.5 g(99%) of product as an off-white solid: ¹ H NMR (CDCl₃, 60 MHz) δ9.7 (s,1H), 8.7 (d, 1H), 8.0 (dd, 1H), 7.1-6.8 (m, 3H), 2.0 (s, 3H); MS m/z 249(M+), 204 (base peak).

3,7-Difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-one

2-(2-methyl-4-fluorophenyl)-5-fluoro-3-pyridinecarboxylic acid (8.5 g,0.034 mol) was placed in 102 g of polyphosphoric acid and heated at 210°C. for 3 h. The reaction was allowed to cool and was then poured into500 mL of ice water. Ethyl acetate and 1N aqueous sodium hydroxide (200mL each) were added and the solution was filtered through Celite. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (2×75 mL). The combined organics were washed withsaturated aqueous sodium bicarbonate and water, dried (MgSO₄), andconcentrated in vacuo leaving 4.0 g of a greenish solid.Recrystallization from ethanol/ethyl acetate with carbon treatment gave2.1 g of clean product: mp 155°-157° C.; ¹ H NMR (CDCl₃, 60 MHz) δ8.3(dd, 1H), 7.4 (dd, 1H), 7.2-6.8 (m, 2H), 2.7 (s, 3H); IR (KBr) 1730,1470, 1280, 785 cm⁻¹ ; MS m/z 231 (M+), 203 (base peak); Analysiscalculated for C₁₃ H₇ NOF₂ : C, 67.54; H, 3.05; N, 6.06. Found: C,67.20; H, 3.20; N, 5.76.

3,7-Difluoro-9-methylspiro[5H-indeno[1,2-b]pyridin-5,4'-imidazolidine]-2',5'-dione

3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-one (2.0 g, 0.0087 mol),potassium cyanide (2.5 eq, 0.022 mol, 1.4 g), ammonium carbonate (4 eq,3.3 g), and 50 mL of ethanol were placed in a sealed bomb and heated to115° C. for 24 h. The bomb was cooled to room temperature and thecontents were filtered through Celite washing with water and ethylacetate. The filtrate was concentrated in vacuo and the residue wasdissolved in 50 mL of 1N aqueous sodium hydroxide and washed with ethylacetate (2×30 mL). The aqueous solution was acidified with concentratedhydrochloric acid and extracted with ethyl acetate (2×50 mL). Theorganics were dried (MgSO₄) and concentrated in vacuo to give 600 mg ofa crude tan solid. Recrystallization from ethanol gave 250 mg of pureproduct: mp<320° C.; ¹ H NMR (DMSO-d₆, 200 MHz) δ11.42 (s, 1 H,exchangeable), 8.66 (s, 1H, exchangeable), 8.60 (m, 1H), 8.17 (dd, 1H,J=2.7 and 8.2 Hz), 7.37 (dd, 1H, J=2.3 and 8.2 Hz), 7.24 (dd, 1H, J=1.7and 10.3 Hz), 2.79 (s, 3H); IR (KBr) 3200, 1710, 1390, 1130 cm⁻¹ ; MSm/z 301 (M+); Analysis calculated for C₁₅ H₉ F₂ N₃ O₂ : C, 59.81; H,3.01; N, 13.95. Found: C, 59.86; H, 3.17; N, 13.67.

EXAMPLE XXXVIII General Procedure for the Synthesis of3,7-Difluoro-9-Methylspiro[5H-Indeno[1,2-b]Pyridin-5,3'-Pyrrolidine]-2',5'-Dione##STR202## Treatment of3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-one with hydrazine inhot diethylene glycol provided3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridine. Deprotonation usingn-butyllithium in tetrahydrofuran followed by reaction with carbondioxide and methanolic hydrogen chloride provided3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-carboxylic acid methylester. The ester was then deprotonated using a slight excess of sodiumhydride in tetrahydrofuran and treated with iodoacetamide to provide,after 18 hours at room temperature and 6 hours at reflux, the titlecompound.

Of special interest according to the present invention aretetrasubstituted compounds of the formula: ##STR203## wherein t isselected from the group consisting of NH, O, S and CHR wherein R' ishydrogen or lower alkyl of 1 to 5 carbon atoms. Especially preferredcompounds are those where the fluoro and methoxy substituents arelocated in the ring in meta position to each other.

An especially preferred compound is 2,7-difluoro-4,5-dimethoxyspiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione of the formula: ##STR204##

This compound is a very potent aldose reductase inhibitor with an IC₅₀value of 0.78×10⁻⁸ Mol/L. The IC₅₀ value is based on the inhibition ofrat lens aldose reductase.

The above compounds are prepared from trifluoro-5-hydroxyfluorenone byreaction with alkali metal alkoxide in a solvent such as dimethylformamide followed by alkyl iodide to provide thedifluoro-dialkoxyfluorenone in good yield. Subsequent conversion to thehydantoin can be carried out using standard Bucherer-Bergs conditions asdescribed herein to produce the desired product in good yield.

EXAMPLE XXXIX 2,7-Difluoro-4,5-Dimethoxyfluorenone

A mixture 2,4,7-trifluoro-5-hydroxyfluorenone (2.5 g, 10 mmol) andsodium methoxide (6 mL of a 25% solution in methanol, 3 eq) in drydimethylformamide (80 mL, over sieves) was stirred under nitrogen atroom temperature. After 2 h, additional sodium methoxide (6 mL of a 25%solution in methanol, 3 eq) was added. Stirring was continued for 2 h atwhich time the mixture was treated with iodomethane (15 mL, 46 mmol 4.6eq) over 20 min. The reaction became a deep red and was then dilutedwith water (300 mL), neutralized with 1N aqueous hydrochloric acid, andfiltered, washing with water. The solid was dissolved in warm ethylacetate (500 mL), dried (MgSO₄), treated with carbon (Norit A), filteredthrough celite, and concentrated. The residue was recrystallized fromethyl acetate.hexane to provide 2.2 g (80%) of product as a red solid:mp 185°-187° C.; IR (KBr) 1722.0, 1615.3, 1487.4 cm⁻¹ : ¹ H NMR(CDCIl₃,200 MHz) δ6.99 (dd, 2H, J=2.3, 6.4 Hz), 6.76 (dd, 2H, J=2.3,10.7 Hz), 3.90 (s, 6H); MS m/z 376 (M+). Anal calcd for C₁₅ H₁₀ F₂ O₃ :C, 65.22; H, 3.65. Found: C, 65.31, H, 3.79.

EXAMPLE XXXX 2,7-Difluoro-4,5-dimethoxyspiro (9H-fluorene9,4'-imidazolidine)-2',5'-dione

A mixture of 2,7-Difluoro-4,5-dimethoxy fluorenone (1.5 g, 5.3 mmol),potassium cyanide (1.4 g, 21.2 mmol, 4 eq) and ammonium carbonate (1.5g, 15.9 mmol, 3 eq) in 70 mL of ethanol was heated in a sealed bomb at114° C. for 18 h. The bomb was then cooled and the mixture partitionedbetween 1N aqueous sodium hydroxide (100 mL) and a 1:1 mixture of ethylacetate/hexane (100 mL). The basic aqueous phase was separated and theorganic phase was extracted with 1N aqueous sodium hydroxide (3×74 mL).The combined basic aqueous layers were washed with ether (2×100 mL),dried (MgSO₄), treated with carbon (Norit A), filtered through celite,and concentrated to provide 1.37 g (70%) of crude material. Thismaterial was combined with an additional 425 mg of crude materialobtained in the same fashion and first leached with ethanol and thencrystallized from ethanol to provide 1.5 g (58%) of product as a whitesolid; mp>326° C.; IR (KBr) 3328.6, 1779.3, 1715.1, 1607.4 cm⁻¹ ; ¹ HNMR (DMSO d₆, 200 MHz) δ11.24 (a, 1H, D₂ O exchangeable), 8.64 (s, 1H,D₂ O exchangeable), 6.96 (m, 4H), 3.87 (s, 6H); MS m/z 346 (M+), basepeak 275. Anal calcd for C₁₇ H₁₂ N₂ O₄ F₂ : C, 58.96; H, 3.49; N, 8.09.Found: C, 59.01; H, 3.59; N, 8.09.

I claim:
 1. A compound of the formula ##STR205## wherein t is selectedfrom the group consisting of O, S and CHR' wherein R' is hydrogen orlower alkyl of 1 to 5 carbon atoms.
 2. A compound according to claim 1wherein the fluoro and methoxy substituents are located on the rings inmeta position to each other.
 3. A pharmaceutical composition for thetreatment of complications of diabetes mellitus in humans comprising aneffective amount of a compound of claim 1 and a pharmaceutical vehicle.4. A composition according to claim 3 wherein the concentration of thecompound in the vehicle is at a level ranging from about 0.5 percent toabout 90 percent by weight.
 5. A method for the treatment ofcomplications of diabetes mellitus in humans and animals comprisingadministering thereto a composition of claim
 3. 6. A method according toclaim 5 wherein the composition is administered in oral form.
 7. Amethod according to claim 5 wherein the composition is administered in adosage amount of about 0.1 mg to about 10 mg/kg of body weight per day.